September 21, 2020

Cholesterol

#129 – Tom Dayspring, M.D.: The latest insights into cardiovascular disease and lipidology

Atherogenic lipoproteins are really the issue behind clinical atherosclerotic vascular disease. … The data has just become so overwhelming.” —Tom Dayspring

Read Time 24 minutes

World-renowned lipidologist Tom Dayspring returns to give an update on the current thinking in lipidology as a follow-up to his 2018 five-part podcast series. In this episode, Tom discusses the growing consensus that atherogenic lipoproteins are essential drivers of atherosclerotic vascular disease. Tom further emphasizes apolipoprotein B (apoB) and lipoprotein(a) (Lp(a)). He provides insights into risk assessment, including which lab metrics to use, how to interpret them, and the appropriate therapeutic targets. Additionally, Tom discusses the most recent developments in lipid-lowering drug therapies—from the continued evolution of PCSK9 inhibitors, to the latest understanding of EPA and DHA, and the most recent addition of bempedoic acid to the list of  therapeutic agents.

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We discuss:

  • The latest in the field of lipidology and cardiovascular disease [3:45];
  • Apolipoproteins—the key to understanding lipid biology [9:30];
  • ApoB as a preferred metric over LDL-P [16:30];
  • Therapeutic goals for apoB concentration [21:45];
  • Drivers of atherosclerosis [34:15];
  • Overview and current thinking on high density lipoproteins (HDLs)—Is it a useful metric? [37:00];
  • Lipoprotein(a)—the most dangerous particle you’ve never heard of [55:00];
  • Are low density lipoprotein triglycerides (LDL-TGs) a useful metric? [1:13:15];
  • Tom’s preferred lab measurements [1:17:45];
  • The latest in lipid-lowering therapies [1:21:30];
  • The different pathways among various lipid-lowering drugs [1:30:45];
  • The latest on EPA and DHA [1:38:15];
  • Fibrates—an underappreciated treatment for hypercholesterolemia [1:49:45] and;
  • More.
§

The latest in the field of lipidology and cardiovascular disease [3:45]

Many patients are eager for in-depth information about lipidology

  • The first podcast with Tom was the longest Peter has ever done (about 8 hours)
    • It was made into a five-part series (1, 2, 3, 4, 5) that has become very popular; Peter was surprised at the level of interest, but it shows the topic’s broad appeal
  • There have exciting new developments in lipidology and CVD in the two years since the last podcast and we’ll go through those things today

Recent updates in lipidology

  • Atherogenic lipoproteins are really the issue behind clinical atherosclerotic vascular disease
    • The data have become overwhelming, so guidelines reflect this now
    • Atherogenesis is sterol-mediated, but sterols are trafficked within apoB-containing lipoproteins, which is how they are transported into artery wall where they can start the pathological process

Figure 1. The process of atherogenesis.

  • Atherogenic lipoproteins are still diagnosed using various cholesterol metrics, but ApoB is within every guideline now (Allan Sniderman has been advocating for this for a long time)
  • What contributes to the atherogenicity of lipoproteins?
    • TGs have taken center stage – affect concentration and functionality

Figure 2. Lipoproteins trafficking triglycerides.

Figure 3. Lipoprotein structure with high TG levels.

  • HDL is no longer considered informative to use
    • Lp(a) has emerging significance
  • Pharmacology has also advanced 

***

Topics on today’s agenda: 

  • Atherogenic lipoproteins (apoB/LDL-P) are front and center in pathogenesis of CVD
  • Methods of risk assessment (e.g., HDL no longer primary)
  • What’s developed in therapies – more data around ezetimibe, PSCK9 inhibitors, omega 3 fatty acids, and a few other treatments (expanding on what we spoke about with Bill Harris)

 

Apolipoproteins—the key to understanding lipid biology [9:30]

ApoB & LDL-P are used interchangeably, but this is not quite accurate.

{end of show notes preview}

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THOMAS DAYSPRING, M.D., FACP, FNLA

Thomas Dayspring, MD, FACP, FNLA is the chief academic officer for True Health Diagnostics, LLC. He provides scientific leadership and direction for the company’s comprehensive educational programs. Dr. Dayspring is a fellow of both the American College of Physicians and the National Lipid Association. He is certified in internal medicine and clinical lipidology.

Before relocating to Virginia in 2012, Dr. Dayspring practiced medicine in New Jersey for 37 years. Over the last two decades, he has given over 4,000 domestic and international lectures, including over 600 CME programs on topics such as atherothrombosis, lipoprotein and vascular biology, biomarker testing, and women’s cardiovascular issues.

Dr Dayspring is an Associate Editor of the Journal of Clinical Lipidology. He has authored or co-authored numerous manuscripts published across leading journals such as the American Journal of Cardiology, the Journal of Clinical Lipidology, and several lipid-related book chapters. He was the recipient of the 2011 National Lipid Association President’s Award for services to clinical lipidology. [truehealthdiag.com]

Disclosures:

  • Employed full time for last three years by True Health Diagnostics, LLC, which provides biomarker diagnostics and clinical services to clinicians, patients, and healthcare organizations
  • 2017: small consulting project for Abbvie

Tom on Twitter: @Drlipid

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.

18 Comments

  1. Thanks for bringing up bempedoic acid. Drilling down I find its target ATP citrate lyase is dependent on insulin. Perhaps elevated LDL is totally the result of postprandial insulin excursions? It would explain a lot.

  2. I’m sadly one of those genetically pre-disposed indivuals with elevated Lp(a) at 95 nmol/L. All my other metrics are great except for this one which is frustrating.

    Interestingly, no heart disease in my family. Grandparents all died at very old age or non-heart related issues. My current family on my dad’s side have been chronic smokers for decades and are doing well.

    Wonder if there is some other genetic factors that offer cardioprotective effects despite an elevated Lp(a)?

    • How high are your TGs? I wonder if elevated LP(a) cause an elevation in TGs.
      Probably the facts that your family is slim, has no diabetes history and great tobacco tolerance can be considered as genetic and cardioprotective.

  3. I look forward to the day you can get Sam Tsimikas on the show. He’s is a legend in Apo (a) research. I will keep a lookout for my weekly emails to see if you were able to pick his brain for a few hours. As Tom also mentioned he does have an informative twitter feed.

    Good luck,

    Sincerely,

    Eric

  4. The whole discussion on HDL seemed to have left out what *I* thought was the primary reason to test for HDL: It’s a biomarker that indicates whether one is getting sufficient amounts of aerobic exercise, at least, when one’s general metabolic efficiency is working properly. The more aerobic activity one does, the higher one’s HDL tends to be. If HDL starts to drop asynchronously with exercise, it may be an indicator that something’s wrong somewhere in the metabolism.

    I’ve never heard of any *other* benefit to measuring HDL, so all this talk in the podcast about not really knowing the functional behavior of HDL felt like it was missing the whole point of measuring it.

    • Dan: You need to be more precise with your terminology. I presume you are inquiring about measuring HDL-C, or perhaps HDL-P metric. HDL is not a a biomarker or a lab test: as its name implies it is a lipoprotein. There are numerous and specific laboratory metrics that may characterize certain aspects of HDLs. HDL-C is the mass of cholesterol molecules trafficked by all of the HDL that exist in a deciliter of plasma. There is zero evidence that CV or other health benefits (outcomes) which are related to exercise can be predicted by baseline HDL-C per se or more importantly judged by any exercise induced changes in HDL metrics. Your premise is old-time conjecture which is not supported by therapeutic outcome trials. Low HDL-C in lipid-drug naïve patients basically serves as a guestimate warning that apoB (atherogenic particle number) may be elevated. Far more accurate and telling to simply measure apoB. T Dayspring

      • while you’re obviously correct, the results shown by Quest lipid panel doesn’t differentiate. It just says “HDL” with a value. In my case, my latest labs indicated 61, which was at the low end of my typical range, typically, between 60 and 80. Here’s why I ask: Over the past 20 years, the duration and intensity of exercise has varied, depending on life circumstances, and HDL levels always moved in parity. The more intense the exercise, the higher the HDL levels. Periods of dormancy, they dropped. Since the pandemic, I’ve been stuck at home, so my exercise (outdoor running) increased from 3mi/day to sometimes over 10mi/day. Over that period of incremental progression, my HDL levels have dropped — for the first time, it’s inverted to the exercise levels.

        I am well-aware of your position that there is no known proven benefit to elevated HDL — but again, I’m not saying there is. I just find it interesting that I see this new inversion of HDL to exercise, and therefore, think measuring HDL may be an early indicator of something else going awry.

        For what it’s worth, I just had my doc order the Quest “Cardio IQ” panel, which gets the various lipid sizes, and my HDL “large” quantity is 6274nmol/L. Their range says this is “medium risk.” (I’ve never had this panel done before, so I have no historical data.)

        To flesh out the picture, during this same period, my LDL has risen from 67 to 92. Again, this is an inversion to its trend for greater exercise.

        I’m 57 and a Type 1 Diabetic: A1c is 5.9 and I’m in-range 95% of the time, and my SD ranges from 18-30.

  5. Dan you are not alone, and I’m glad you asked that question. These are my notes from A&P II class before nursing school: “HDL moves fat into the cell. Lo LDL and lo HDL is a good diet and not exercising. HDL is produced if we are active.” So you have a lot of company Dan! Thank you Thomas Dayspring for answering, too. Over the years, I’ve started to think that there’s likely much more to HDL than my clunky A&PII notes, thanks to people like TD and PA. About 8 years ago, my HDL (C) was consistently at around 67. But the last 2-4 years, it’s in the high 80s or 90s. Why? What does it mean? Good? Bad? Indifferent? I have no idea. I have done the HDL P test one time, and it was 42.7.

  6. I know we got into Lp(a), Apo (b) research, but I’m still wondering how a lot of this might fit into the studies at show optimal cholesterol levels for mortality are a lot higher than what pretty much every doctor uses when looking at patients.

    This would be the example: https://www.nature.com/articles/s41598-018-38461-y
    “Total cholesterol and all-cause mortality by sex and age: a prospective cohort study among 12.8 million adults”

    I know it was mentioned that cholesterol in serum would be insignificant to cholesterol in actual cells, and that we want to get levels of cholesterol (Apo (b) ) at levels like a child (not sure if i’m misquoting Tom here, I’m not a science expert)

    If we are doing things to lower Lp(a) or Apo (b), wouldn’t our total cholesterol be going down and might that be knocking us our of the range of total cholesterol that isn’t optimal for longevity (despite what Peter mentioned in terms of Apo (b) being a much better marker to look for diagnostics in patients. I definitely don’t want to increase death at the expense of lowering my chance of heart disease.

    There have been studies as well that show that higher cholesterol (not sure levels) in older individuals 68+ might actually be better than lowering as well…
    https://www.jwatch.org/na50908/2020/02/13/another-study-cholesterol-older-patients.

    I’m only 40, so I don’t have the above issue, but I’m looking to the future.

    Great podcast by the way!

    • The studies finding death and events to be associated with high TC or LDL-C in the elderly are the result of “reverse causation:” years before disease is diagnosed, premorbid conditions (including both Alzheimer’s and undiagnosed cancer) and frailty cause a reduction in LDL-C levels, creating the illusion that these diseases are *caused* by low levels of LDL-C.

  7. I am one of the lucky ones with LPA mutation too….although my Lp(a) is even higher: 186 nmol/L. I inherited it through my mom’s side of the family, as we both did 23andme and we both have the same mutation, my father does not. My mother is 83, has high blood pressure and T2DM. Her cognition is excellent though so she must have decent cerebral blood flow. I suspect she inherited from her mother, who did die of a MI in her 70s, while her father who smoked and drank lived to be almost 90. So clearly, as mentioned in the podcast, Lp(a) does not have to be a bad actor at early age.

    I think it is all about polygenic risk. Death by a thousand cuts, so to speak. LPA mutations alone are not enough to load the gun and pull the trigger. Some people get dealt an unfortunate hand at birth: mutations in TNF-alpha and IL6 (and others) that make them prone to higher levels of inflammatory cytokines, mutations in their anti-oxidant defense genes (GPX, GSR, CAT, SOD, GSTT, GSTM), likely APOE and other lipid and various lipase genes, mutations in endothelial health genes like NOS3, biopterin synthesis and recycling; and on and on. You get the idea. Then of course you have lifestyle contributing too. Conversely others are luckier…they might have elevated Lp(a) but a downregulated inflammasome and upregulated or optimal anti-oxidant plus other ideal gene combinations to render Lp(a) less harmful. I must be in that latter category.

    I was bummed when I found I had high Lp(a) and a CIMT that showed I had the arteries of someone 20 years older. But it got me onboard to a WFPB diet, sustained release niacin, transdermal estrogen plus other things. I plan on repeating my CIMT next year to see what changes have happened.

  8. Where does the TG/HDL-C ratio fit into the routine tracking as it is readily available on a basic lipid panel? I understood it had good predictive power with respect to LDL particle size and number. But HDL being in the ratio implies HDL matters. With dietary controls (primarily elimination of simple carbs and TRE) my fasting TG is generally around 70 vs 210 prior, and HDL is now in 50s vs prior mid 30s. Just ordered ApoB test. Thanks for great discussion.

  9. Thank you for both. Interesting as usual.

    In the UK, the NHS still sending us usual lipid panels with no opportunities to measure ApoB or a one off Lp(a). We had Non HDLc added few years ago.

  10. This podcast was a good follow-up to the first one I listened to with these two gents.

    The topic of genetics in relation to CVD (e.g., familial hypercholesterolemia) would be interesting. This was mentioned at the end of the podcast because I have been diagnosed with familial hypercholesterolemia. While this diagnoses remains, neither CVD or heart attacks pervasively exists in my family. High blood pressure, however, does on one side. Thus, my gift in life.

    FH was originally found after a VAP blood panel wherein my LDL-C was 269 mg/dl. Once my cardiologist and lipidologist saw this their concern was verbatim. No genetic tests have been performed. Interestingly, from the VAP, my Lp(a) measurement is 3 mg/dl. Triglycerides have always been ~100 and PLAC Lp-PLA2 was just under 200 nmol/min/dl. A later Angiogram, perhaps predictably, showed almost nothing regarding obstruction. Physical inspection, no xanthomas.

    Thus, here I am with, seemingly, a mixed bag of good and bad genetics. My body loves to have high cholesterol; eating cardboard would probably cause my cholesterol to be high. Yet, it seems interesting that perhaps other genetics or past metrics suggest this excessive cholesterol has not cause any problems, SO FAR. Thus, I have been increasingly interested in the constellation of genetic factors that contribute to someone having a higher risk for CVD/heart attacks. I’ve come to think that it’s not a single factor such as ENOURMOUSLY high LDL-C. Rather, is it the profile of one’s genetic factors that contribute to their risk?

  11. Any recommendation on which ApoB 100 test to get? I see one from LabCorp that is listed as an immunologic test and one from Quest that is nephelometry. Do these different methods vary enough to make me want one vs the other?

  12. Peter and Tom: you both expressed surprise that the STRENGTH CV EpaNova (EPA+DHA) trial was stopped early. From the beginning, the rationale for Vascepa’s EPA-only formulation was the studies finding that DHA elevates apoB (and in studies where apoB is not measured, LDL-C), including one by Bill Lands:
    https://pubmed.ncbi.nlm.nih.gov/2375788/
    … whereas most studies have not found this for EPA; some studies have done so, and even found the reverse:
    https://academic.oup.com/ajcn/article-abstract/52/4/632/4650895?redirectedFrom=fulltext

    … but REDUCE-IT clearly found a reduction with EPA-only, and was much larger than any of the previous trials with EPA and/or DHA that had looked at apoB. Bill Lands pointed out on the pod that the apoB-boosting effect of DHA might only occur under the conditions he studied (high-dose, and in patients with very high TG), but some studies have found it in other populations and a low dose:
    https://pubmed.ncbi.nlm.nih.gov/15051597/

    In any case, the conditions in Bill’s study (high-dose omega-3 in patients with elevated TG) are exactly the conditions in REDUCE-IT and STRENGTH CV.

    A somewhat weaker summary of the data (by authors with ties to Amarin) that would still be consistent wth EPA-only being superior to DHA (conceivably enough to make DHA ineffective if it has other comparative disadvantages):
    “EPA has been shown to cause numerically greater reductions in ApoB than products containing both EPA and DHA in patient populations with high or very high triglyceride levels, although additional head-to-head studies are needed to further differentiate the effect on ApoB [63], [67], [76], [77], [78].”
    https://www.sciencedirect.com/science/article/pii/S1537189116303147

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