June 26, 2012

Cardiovascular Disease

The straight dope on cholesterol – Part VIII

In this post we'll double-click on a paper covering cholesterol and heart disease risk factors.

Read Time 10 minutes

Last week the Journal of the American Medical Association (JAMA) published an article titled Lipid-Related Markers and Cardiovascular Disease Prediction, which you can download here.  This is quite timely as we are in the midst of our series on cholesterol and heart disease risk factors.

I was planning to write a post on my interpretation of this report, as I know many of you have questions about it, when I was reminded of one of my favorite principles in life: never be afraid to outsource to those more qualified.

While there are many folks more qualified than me to address this entire topic of cholesterol and heart disease risk, there are a handful who have always been very generous with their time and insights on this subject and who I consider mentors on this topic.  This list includes Drs. Tom Dayspring, Tara Dall, Allan Sniderman, and Jim Otvos.

Below are excerpts of comments from Drs. Dayspring and Dall, followed by the comments of Dr. Sniderman, with my comments interspersed for clarification.


Initial response by Drs. Dayspring and Dall

The authors from the The Emerging Risk Factors Collaboration (ERFC) conclude:

In a study of individuals without known cardiovascular disease (CVD), the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein associated phospholipase A2 (Lp-PLA2) mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction.

In other words, the authors concluded that advanced lipid testing, beyond “just” LDL-C, HDL-C, TG, and total cholesterol did little to help predict heart disease in people without a known history of heart disease.

The accompanying editorial by Dr. Scott Grundy (the former NCEP chairman) raises several flaws of the analysis including old apoB data where studies used primitive and non-standardized apoB assays as well as the use of out-dated older risk assessment tools established 20-30 years ago when cardiac disease manifestation and presentation were very different than today.

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 apoB) are correlated.  However, 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, yet have little 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. However both AMORIS (which somehow was not included in this analysis) and INTERHEART — two very large 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 medications 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, such as highly sensitive C-reactive protein (hs-CRP), 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 obtain more resolute lipid and lipoprotein goals of therapy, not per se any (still nonexistent) inflammatory goals of therapy. However, current studies do suggest further studies will be needed to show if it is important to also normalize at least some inflammatory markers.

The JAMA study states:

The addition of the combination apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipaseA2 (Lp-PLA2) to risk scores containing total cholesterol and HDL-C provided slight improvement in CVD prediction.

When you apply that slight improvement to 300 million Americans you are talking about millions of persons who would indeed benefit.

Interestingly, last year the NLA reviewed all of these data, and much 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 (most adults over 40 years of age).

Subsequent response by Drs. Dayspring and Dall

This study combined data from 37 prospective cohort studies where plasma apolipoprotein levels were measured at baseline in patients followed for an average of 10 years. They conducted 2 analyses:

  1. One which used apolipoprotein B (apoB), apolipoprotein A-I (apoA-I), lipoprotein(a) (Lp(a)), or Lp-PLA2 instead of total cholesterol (TC) and HDL cholesterol (HDL-C), and
  2. One using the alternative biomarkers in addition to TC and HDL-C.

They concluded that replacement of TC and HDL-C with apolipoproteins or their ratios was not associated with improved cardiovascular risk prediction, whereas adding lipoprotein factors to TC and HDL-C was associated with slight improvement in risk prediction.

Several previous epidemiologic studies have demonstrated that apolipoproteins, including apoB, may be as good as, and often better than, LDL-C , non-HDL-C and cholesterol ratios for estimating coronary heart disease (CHD) risk. In a previous meta-analysis assessing the association between baseline apoB levels and CHD risk from 19 prospective studies with follow-up of 9 years, apoB was a significant predictor of CHD, with an overall relative risk of about 2 (i.e., double the risk) for the upper tertile (i.e., upper third of the population) compared with the lower tertile.

Non-HDL-C has been suggested as a potential surrogate for apoB. However, while non-HDL-C and apoB are highly correlated they can also be discordant in many patients, including those with and without metabolic syndrome, as shown here and here.

Clinical trials showing that apoB was superior, even to non-HDL-C, in predicting risk for CHD are numerous, including AMORIS, Leiden Heart Study, AFCAPS/TexCAPS, LIPID, Health Professional Follow-up Study, NHANES, The Chinese Heart Study, Framingham Offspring Study, Cardiovascular Risk in Young Finns, INTERHEART, and IDEAL (summarized here).

Strong evidence now also exists that cardiovascular disease risk tracks with LDL-P/apoB (not LDL-C) in patients with discordant levels of these markers. Discordance analyses in the MESA study show that LDL-C over- or underestimated LDL-related risk in many patients, leading to suboptimal LDL management.  This recently published study in JAMA did not account for specific groups that were discordant but looked only at the population as a whole.  Remember physicians do not treat populations; they treat individual patients, one by one.

How can a physician know if a patient is discordant if they do not measure apoB or LDL-P?  To restate the point, another limitation of this study is that it did not include studies that used LDL-P analysis.

Most physicians view it as their goal not to miss one patient who could benefit from preventive therapies through lifestyle and counseling interventions or medications proven to reduce cardiovascular (CV) risk in the primary prevention setting.

Multiple organizations support the use of apoB level as both marker of CV risk and treatment goal. Current Canadian lipid guidelines have incorporated apoB as an alternate primary target of therapy due to the wealth of data supporting apoB in CV risk prediction. The American Diabetes Association and American College of Cardiology consensus statement in 2008 also recommended apoB as a target of therapy in those with high cardiometabolic risk.  Furthermore, as part of the comprehensive diabetes care treatment goals, the American Association of Clinical Endocrinology published recommendations for apoB as another target of therapy in addition to LDL-C, Non HDL-C, HDL-C and triglycerides.  The recommendations from AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices also list goals of therapy for apoB and LDL-P.

The JAMA study in question included studies from 1968 to 2007. ApoB assays have improved significantly over the years, as early assays were more primitive, non-standardized, and therefore less reliable. The study authors recognize this limitation in their comment section and it was also addressed in the accompanying editorial by Dr. Scott Grundy, the former NCEP chairman.  He highlighted several other flaws in the analysis including the use of out-dated risk assessment tools established 20-30 years ago when coronary artery disease presentation was very different to today. In addition, correct interpretation of the study findings is difficult without consideration of treatment differences among the patients included in the study (e.g., patients with multiple high risk markers may have been treated more aggressively, resulting in fewer events).

As a practicing physician, I have used apoB/LDL-P for more than a decade in order not to miss any patient that could be at risk and might benefit from preventive therapy.  I do not want any of my patients to become part of the national statistic:

50% of people with heart disease have normal traditional lipid values.

Population studies have diluted relevant clinical meaning to physicians treating individual patients. Clearly a better measure is needed to understand risk in individual patients. Randomized controlled clinical outcomes trials in children are rare, but does that mean we don’t treat children or young women?  ApoB and/or LDL–P can help physicians target which of those primary prevention patients need more aggressive lifestyle or medical therapy.

Conversely, it is also important not to over-treat patients with high cholesterol who in fact may not have apoB, LDL-P or lipoprotein (a)-related risk.  It may also not be cost-effective or even reasonable to treat such patients based on cholesterol levels. The key is early detection for effective prevention. After very careful review of all the published studies to date, the National Lipid Association’s published consensus on advanced biomarker testing in 2011 recommends that, except in the lowest risk patients, apoB and LDL-P should be considered in most patients for both risk assessment as well as ongoing clinical management.

On the other hand, apoA-I is minimally useful as a test in isolation as there is not a one-to-one relationship between each HDL particle and apoA-1 (as there is for an LDL particle and apoB). As there may be several apoA-I apolipoproteins on each HDL particle, measuring apoA-I alone will not accurately quantify HDL-P.  HDL is incredibly complex and the functionality of the HDL particle will likely be the focus of future assays and studies.  For example, the use of apoA-I as a tool to diagnosis familial hypoalphalipoproteinemia is very helpful.  This condition is very difficult to treat clinically but is an important secondary cause of low HDL-C that should be ruled out. Additionally, in both the INTERHEART and AMORIS studies the best predictor of cardiovascular risk was the apoB/apoA-I ratio.

Lipoprotein associated phospholipase A2 (Lp-PLA2) is an inflammatory marker, not intended for use as a “stand-alone” marker to assess cardiovascular risk, but in combination with other lipoprotein-based tools (e.g., apoB and LDL-P).   It is well recognized that inflammation plays a role in atherosclerosis.  Currently accepted methods of assessing inflammation such as high sensitivity C reactive protein (hs-CRP) may be elevated in many disease states including, but not limited to, vascular disease. Furthermore, hs-CRP levels may also fluctuate greatly so multiple measurements are typically required.  I have always considered Lp-PLA2 to be a superior marker of vascular disease or what I consider “angry arteries.”  When Lp-PLA2 is elevated, treatments aimed at reducing inflammation (e.g., dietary modification, omega-3 fatty acid supplementation, smoking cessation) become important.  Clinically, high levels of Lp-PLA2 indicate that the disease process has not been effectively halted — arterial plaque may still be actively forming — and more aggressive treatment is required as unstable plaque may be present. Lp-PLA2 is not meant to be used as a marker in isolation or to replace other traditional methods of risk assessment.  However, it greatly augments the utility of the latter, and is a very useful tool to guide us in ongoing treatment decisions.

Until levels of a patient’s biomarkers lie within the optimal range, it is not clear that their risk has been eliminated.   If our goal is to reduce the epidemics of cardiovascular disease and diabetes, we need to be aware of the role lipoproteins play in cardiovascular and diabetes disease prediction and continue to carry out research to find better ways of detecting disease at earlier and earlier stages.

Additional commentary by Dr. Sniderman

In the JAMA study the average non-HDL-C was 175 mg/dl, which is the 82nd percentile of the U.S. population whereas the average apoB was 110 mg/dl, which is the 67th percentile. They should match, but they do not. Obviously, some populations have higher non-HDL-C than Americans. The Swedes, for example, certainly do. But the Swedes have higher apoB levels to match.  No population that I have ever seen has values this discordant, which means their lipoprotein composition is different from any I have ever seen.  This raises the question as to how accurately apoB was measured. From Table 1, of the 26 studies with data on apoB, blood was collected in 1 starting in 1968, in 1 in 1970, in 9 in the 1980’s, in 8 in the early 1990’s.

When were the apoB’s measured in relation to when they were obtained?  We don’t know.  Reading the original papers, in the great majority, measuring apoB was not part of the protocol.  For 13 of the studies, no methods are listed and another 5 are listed as in-house assays (i.e., non-standardized). None of these can have standardized results. Nor are they necessarily accurate. Even the studies employing commercial assays were not necessarily standardized.  The actual average values for apoB are listed in Table 1 and, not surprisingly, they are extraordinarily variable. These are mainly European studies and the average apoB ranges from 0.86 to 1.33 with many of values in the 1.0 to 1.2 range. This variance exceeds anything I have ever seen and anything that I think is epidemiologically possible.

The trends can be compared within studies but the problem is that this is a patient level study, which means all of these different results from all of these different assays are mixed together. How do you mix apples and oranges and nuts and pineapples and pretend they are all cherries? Obviously, you can’t. If you did not measure something accurately, if the results from the different studies differ so radically, how can they be lumped together?

What ERFC claims is the strength of their study is actually its weakness.  Our meta-analysis was done at the study level. All the studies in our meta-analysis were published and therefore all the methods to measure apoB are listed. There are two sources of assay error: imprecision (lack of reproducibility) and inaccuracy (lack of standardization). Study level analyses are certainly affected by imprecision but not so much by inaccuracy since the trends in each study are what is quantitated. This means our design, in this instance, is stronger than their design.

The irony of this analysis is that the assays for apoB have been standardized and are precise accurate but require the use of a standardized assay. LDL-C has not been standardized and the errors in measuring LDL-C are much more substantial than the errors in measuring apoB. ApoB is measured much more accurately and precisely in clinical practice today than it was measured in the research studies in ERFC. ApoB was evaluated in this study based on methods that no one would use today.

If one accepts ERFC, then total cholesterol is just as good as LDL-C, non-HDL-C and apoB.  This is not a reasonable conclusion. What does this imply about the studies that showed LDL-C was better than total cholesterol (TC) and the studies that showed non-HDL-C was better than LDL-C and the studies that showed apoB was better than LDL-C and non-HDL-C?  It’s hard to imagine, based on the conclusions of the ERFC, that we should go back to using TC as the screening tool for CV risk.

On page 2501, ERFC writes: “replacement of information on total cholesterol (TC) and HDL-C with apolipoprotein B and A-I significantly worsened risk discrimination and risk classification.”  However, look at Figure 1. What happens when TC and HDL-C are replaced by the TC/HDL-C ratio? Taking out the numerator (TC) and the denominator (HDL-C) and putting in the ratio (TC/HDL-C) is the worst thing one can do. The c-index change is -0.0098 — more than three times worse than with apoB, and net reclassification is much worse also. How can the way the same numbers are entered make such a difference?

The current study published in JAMA does not create a compelling case to abandon the use of advanced lipid testing in favor of standard testing.  It suffers from many methodological flaws and, upon careful examination in the context of the entire body of literature, actually reinforces the need for lipoprotein testing in all but a select few patients.

Photo by Joshua McKenty is licensed under CC by 2.0

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  1. I think the axiom: Garbage In = Garbage Out is the story of the day here. There is no way to get good correlations to variables that are not measured with any standard references. They used too many studies with non standard data and more than likely this washed out any chance of finding a reasonable correlation. The devil is in the details, as usual.

  2. OMG, we are in the midst of this series still?
    I am one of those people who is impatient to find out the end of the story.
    Luckily it is an interesting story so far, and this looks like one of the most exciting chapters: there is nothing like a bit of personality and disagreement to spice things up: good choice for a mid-series diversion.

  3. Dr Dayspring hits it on the head: Individuals are being treated, not populations; and how else to discover discordance unless you test, and if discordance discovered treat people who otherwise might not be treated and who might not only incur disease, but suffer events. I am one who favors testing having been discovered to be discordant. I believe that discordance may be the reason for CAD in my family(not hyperfamilial) and wish I found a doc like Dr. Dayspring much earlier. All looked at my Fredenwahl calculated scores and said how great my numbers were especially the LDL of 75 and Trgs of 75! No need for treatment or worry with a family history so I was told. I am afraid not.
    I tell all friends who I learn are put on statins by their docs whether they have had an NMR. Answer regarding the last 6 or so people: no, doc just said i need the statin. Well, I hope they do not have a discordance issue.

  4. First of all, thanks for your explanation of cholesterol measuring. It is the first blog post that I have seen explaining it clearly.

    Second, my impression as engineer. Since I have clicked on two or three links, perhaps I have sampled the faulty ones, but it seems to me that most if not all of the studies referenced by you and Hasan Hanachi focus on CVD with main study outcome fatal or non-fatal cardiac event. I cannot think of a more misleading measure of efficacy of a treatment goal for one patient, since it may actually decrease his/her longevity and/or quality of life (I don’t think statins improve this). This is a sign of our times, I suppose. A cardiologist will be happy if their patients don’t die of heart disease while they die of something else. Sometimes overall mortality and CVD mortality will drive the same results, sometimes not. I think that the second and third figures of the Norwegian HUNT 2 study illuminates my point: I am on the >7mmol/l quartile and I am not driven to do anything about it (I am quite low-carb focused already).

    Third, I have done a quick google of “apoB any cause death” and at least there seems to be two different prediction of death powers of apoB depending upon kind of population: none in two studies, one with cardiac patients and one with kidney patients; quite predictive in one study with diabetic type I patients. I couldn’t find any with a drug naive population (my fault, sure): is there any?

    • I have located another study.

      A study analyzing the NHANES III data arrived to some hazard ratios per standard deviation increment for some measures, although they were not drug naive. In table 2 all causes of death are evaluated giving rise to every one of the hazard ratios 95% confidence intervals including the neutral result, 1. Borderline on significance (95% confidence interval almost not containing the unity) were HDL-C 0.87 (0.72,1.04), LDL-C 0.9 (0.81,1.01), TC/HDL-C 1.04 (0.98,1.08) —this last one was also the narrowest—. ApoB hazard ratio was 1.17 (0.83,1.64), it’s a quite wide confidence interval pointing toward a not too high sensitivity as a measure for longevity.

      Not that I dismiss what information ApoB can add to the picture of the health of a patient, but it seems to me quite dangerous if it drives him/her toward the medication route (statins).

      By the way, I have been unable to locate the feed for all the comments, only for the comments of each one of the blog entries.

  5. Speaking of studies, have you seen the recent one by Dr. Ludwig? (https://www.webmd.com/diet/news/20120626/all-calories-not-created-equal-study-suggests) The sample size is very small so it seems hard to draw strong conclusions. From what I read, it suggests that low fat diets are bad (no surprise there), low carb diets are best at weight reduction but low glycemic index diets are better for health as they have lower inflammation and cortisol. Would love to hear your thoughts.

    • Hi Anon:

      “low carb diets are best at weight reduction but low glycemic index diets are better for health”

      Even this is an argument in favor of the current Atkins diet. Look carefully at the so-called “carb ladder” constructed by Dr. Eric Westman in the current book (NANY) for phase 2, known as OWL. You’ll see that ladder very closely follows the glycemic index, with minor deviations. The current Atkins diet combines the best of both low-carb & low-glycemic.

    • Regarding the so-called high levels of CRP, it only came about after the researchers tortured the data with statistical manipulation. Read the comment at the top of the page https://forum.lowcarber.org/showthread.php?t=443836&page=2 to get a detailed understanding. This is just one more example of having a conclusion prior to the experiment, then doing anything possible to justify it. It’s dishonest, and the researchers should be publicly chastised.

      • Jake! Nice to have you back, man! I thought you had vanished into thin air. I’m going to be covering this exact point in this week’s post…

  6. This is exactly what we, the lay public, don’t see when the media reports headlines based on medical journal studies. This critique is an excellent example of such discourse. I am sure that the study authors may have serious rebuttals to these concerns, but the point is that there may be serious flaws in this study and the public should be aware of them.

    As soon as I saw in the abstract that some portion of the sample was based on data from 1968, alarm bells went off in my mind as well, as I was sure that testing accuracy would have greatly improved since then and that data could not be mixed with more modern data. The contributors above added a number of more expert critiques as well.

    Just today, a new Greek study of Swedish women was published (https://www.bmj.com/content/344/bmj.e4026) that claims that low carb diets lead to an increased risk of CVD. This led to this headline: HEART ATTACK RISK IN DIETING and this sub-title “PEOPLE on extreme Atkins-style diets are putting themselves at risk of potentially fatal heart disease and strokes, experts warned yesterday.” (https://www.express.co.uk/posts/view/329161/Heart-attack-risk-in-dieting) However, if you look at the study, the screaming flaw is that they measured LCHProtein diets instead of LCHF! I am sure that there are other issues, but I stopped there. The vast majority of the newspaper reading public will never notice this distinction.

    Thanks again for this site and this level of discourse.

    • Something funky happened in the edit of my last comment, which I see posted under the name of “undefined”. I’m not sure there’s a comment out there in the ethers (but I don’t see it pending moderation), that is an edited comment in my real name, with close to, but not exact, content as the one attributed to “undefined”. The comment started out in my name and posted a couple of times that way thru edits. I think I may have been editing when the clock ran out.

  7. Peter, another great entry to the cholesterol series.

    Was wondering if you could take a brief moment to comment on the new JAMA study out today, comparing very-low-carb vs. low-glycemic vs. low-fat diets.


    Metabolically, the very low carb trounced the competition (unsurprisingly). However, every media outlet is reporting the study with a caveat that C-reactive protein and cortisol (i.e. inflammation) raised significantly on the very low carb, and hence, they cannot recommend the diet.

    My inclination is that this one of the short-term effects of a person acclimating to a VLC diet (a la increased cholesterol in the short-term). Had the study been extended, the cortisol and CRP levels would have eventually stabilized.

    Your thoughts? i already have breathless anti-low-carb friends ready to pounce… 🙂

    • I’ll comment on this in greater detail later. Probably a dedicated post. Tell your friends to read the *actual* study, not the mindless interpretation of the dingle-berries in the press who have bastardized the conclusions to fit their own preconceptions.

    • In the commentary he gave in JAMA, I thought George Bray was going to give himself whiplash with all the ways he was trying to discount the low carb findings. Made me chuckle.

      • Really, really embarrassing. He said, “Adherence is the major key for weight loss and maintenance. There is no magic in any diet.” Even more incredible, was the commentary of Marion Nestle, who took away from this study, “little difference in weight loss and maintenance between one kind of diet and another.”

    • Peter, what set me up for the giggle was he first reviewed the other study published this month on dieting, the STEPS vs. Standard Behavioral Whatever, and concluded that review with a statement to the effect that now if we could only find a diet that people could tolerate for the long term, and I thought, wow cool segway to the low carb study (ok don’t roll your eyes, he *did* renege somewhat on his previous position regarding low carb so I thought maybe he has gotten it), but then he states what an excellently controlled study it was and proceeds to go methods ninja on it! I had to read it twice just to savor the intensity. I didn’t read Nestle’s comment, but I’ll spare myself.

    • I searched the JAMA article but couldn’t find the comments by Bray & Nestle. Are these in a different location? When you are clinging to an outdated paradigm I guess you have to go all in. Do they think that ordinary people (& the media) are stupid and will believe anything they say regardless of the data. My hsCRP was at 0.3 when doing low carb, so personally I’m not seeing an issue. I don’t think I had my cortisol tested but from Peter’s read on the general trend of the data I’m not worried about it. This was a well designed and executed study, even though n=21. I would have like N to be a lot bigger and the duration on each diet longer, but there just is not funding for a study like that.

    • You have to give Bray & Nestle a break. They both have millions of dollars personally riding on the outcome. Bray has a large lab for which he needs to raise money via grants. Nestle was until recently in charge of a whole department of NYU for which she also had to raise money; now she makes sweet bucks writing nutrition books. Their interests are literally vested — in their retirement accounts. Of course they’ll never do anything but fight low-carb. Just understand that they have to protect the paycheck.

  8. More studies! (Peter noted that this one was coming…)


    Conclusion: The results of our study challenge the notion that a calorie is a calorie from a metabolic perspective. During isocaloric feeding following weight loss, REE was 67 kcal/d higher with the very low-carbohydrate diet compared with the low-fat diet. TEE differed by approximately 300 kcal/d between these 2 diets, an effect corresponding with the amount of energy typically expended in 1 hour of moderate-intensity physical activity.

    So a calorie may not be a calorie (sort of…)!

  9. Hi just read the paper by Ludwig one of the other members pointed out. It showed a higher level of cortisol and CRP in patients undergoing a v. low-carb diet – is this concerning to you?
    I’m not too familiar with the biochemical link between ketones and cortisol.

    • David (and others, as I know many of you have this question), I’ll do a post on this study later, but keep the following 2 points in mind:

      1. All 3 groups had about a 50% reduction in hs-CRP!
      2. Don’t confuse “statistical” significance with “clinical” significance. The statistical significance is very minor, at best (p=0.13 overall and p=0.05 for trend), but more importantly, there is probably no clinical significance of 0.78 versus 0.87.

    • I have read elsewhere where CRP increases a bit on low carb, but it was not felt to be related to actual increases in inflammation per other markers, but rather some artifact. It looks like many labs may get skewed with low carb, possibly not all of any clinical significance.

  10. Peter,

    Thanks for continuing the series as I know you’re busy with the new project; best of luck with that. I commented on your Straight Dope VI post and wanted to follow up with the NMR results I told you I was going in for (I repiled on the VI thread but it seems it may be closed…I’m no expert in that regard). Probably won’t surprise you to hear my LDL-P came back high (1611 nmol/L). I hope that as your series progresses, you may suggest some ways to deal with such a potential problem through diet. I’m still not to the point where I want to go on a statin.
    Related to this post, I took some relief in that through a test in December, my CRP was measured to be .3. There are so many variables that its hard to wrap my head around.
    This series is great! Thanks.

  11. Would hope you might provide some clarification: Dr Dayspring in one of his tweets says to note criticism of the study and concern regarding Atkins like diet and heart disease. Elsewhere i have heard him say that moderate sat fat is ok- the key being moderate. Where does he stand on this. My take from your writing is that level of sat fat intake not a concern if LDL-P is at goal. Appreciate clarification. Thanks.

  12. Thank you so much for your work, particularly how it reflects the empirical evidence you derive from practical application of fitness and nutrition principles in your own life. Also your consistently cordial tone with all; that is indicative of a lot I think, as far as your ‘inner’ health. I have one question after reading through all the Cholesterol primers: does Ketogenic living confer some reduction of or exemption from high LDL-P levels? Is there a known mechanism for that? If you have time… again thanks

    • This is a *great* question but, unfortunately, one that no one knows the answer to, as it’s never been studied. I know Eric Westman believes this to be true, and it may well be. There are certainly mechanistic argument that can be made supporting this hypothesis. But it’s still a hypothesis.

    • “I know Eric Westman believes this to be true, and it may well be. ”

      And Peter, I believe Volek & Phinney may share this opinion. So considering we are in an ambiguous situation, who to bet your life on? I’m going with Westman & Volek – Westman has sound clinical experience & Volek has published about 200 papers. They have as much expertise in the keto + heart disease realm as anyone, yes?

  13. Peter: You’ve done a great job with the series so the comments by Dall, Dayspring and Sniderman were as expected and in some cases already discussed! I’ve looked back at Parts IV-VI and started looking at the NLA Biomarker Statement. The diagram in Part IV was shocking to me demonstrating that the disease process can start in preteen years yet it does not seem that we look for it or address it until middle age or in the case of women, post menopause (isn’t that a little late?). In a comment to an earlier post, Dr. Dayspring mentioned that if LDL-P is quite low, there is no disease risk. How would you correlate this to figure from Part IV, no LP rentention ? LP rentention but no foam cells? I.e. where in the diagram would that be represented? If one ate low fat or SAD, can we expect to look like the 20s and beyond photo in our forties? (It seems as if there would already be significant damage for someone in their 40s).

    If diet can affect LDL-P, and one is now on a low to moderate carb diet (50-100g/day) with a “good” LDL-P, how does one go about determining whether or not they have already developed atherosclerosis? (Especially where the former diet was crap for many years). Is lowering LDL-P the best way to “reverse” any atherosclerotic process? Anything additional?

    What other markers/tests, if any, would one with a family history of atherosclerosis want to review/discuss with their physician (especially if the goal is to both maximize longevity and optimize 🙂 ! ). IMT? Other?

    Maybe some of these issues will be addressed in the “what to do about LDL-P” post.

    Great education. Thanks

    • Assuming one does not have any symptoms, the best way to identify “brewing” disease is probably a combination of tests (e.g., calcium score, IMT). The question, of course, is should one bother doing these? My argument, for someone who is asymptomatic and already “maxing” out on the lifestyle choices, is that such tests probably don’t offer much. I think an LDL-P/apoB, coupled with markers of inflammation (e.g., Lp-PLA2, MPO, hs-CRP) is more than enough to determine if medical intervention, beyond lifestyle, is worth it. But now we’re into a grey area with less data.

  14. “. . . not the mindless interpretation of the dingle-berries in the press who have bastardized the conclusions to fit their own preconceptions.”

    LOL! From now on, I’ll think of any of those sensationalized missed-the-mark headlines as just another attack of the dingle-berries.

  15. So exactly what is the status of lipoprotein (a) at present? Is this still considered an independent high-risk factor?

    Mine varies from 700 – 900 over time and as far as I know there is no known way to get it down to within acceptable range.

    • I do not believe it is. Certainly it’s a very atherogenic particle, but I haven’t seen enough data to confirm it’s an independent risk factor. Part of the problem is we don’t have the technology to count Lp(a) particles, only to measure mass and cholesterol content.

  16. Sadly, my mother passed away last week at the age of 91, after she had been to her GP for a checkup. The cause on the DC is listed as Atherosclerotic cardiac disease, with Diabetes Mellitus listed as significant condition contributing to death, but not related to cause given.
    The day before she died, she got a call from the idiot doctor telling her that her blood work was fine.
    If this isn’t proof that the standard lab tests are meaningless, nothing is.
    She hadn’t ever been hospitalized for ACD, but had been taking a statin, high BP meds, Diabetes meds, and an aspirin. RIP, Mom.

    • I don’t rely on VAP or standard panels any longer, so because I’ve switched to NMR, the comparison is not uniform. I’ll update at some point, though.

  17. Hey Peter,
    I was wondering if it could/would be feasible to do lipid panels on “indigenous” folks (aborigines, amazon, inuit, etc.) who have been eating a “palio” type diet their entire life and maybe get some kind of base line for a population who has been on a “lifetime” ketogenic diet.
    Thanks, Diana

    • It’s certainly possible, but it’s not entirely clear how “polluted” their diets have become by Western influence, thereby reducing the difference.

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