240 ‒ The confusion around HDL and its link to cardiovascular disease | Dan Rader, M.D.

Summary

In this episode of The Drive podcast, hosted by Peter Attia, Dr. Dan Rader, a professor of molecular medicine, delves into the intricate biology of high-density lipoproteins (HDL). The conversation explores HDL's role in cardiovascular health, its complex metabolism, and its comparison with low-density lipoproteins (LDL). With a focus on HDL's misunderstood "good cholesterol" label, Dr. Rader addresses genetic conditions affecting HDL levels, the impact of insulin resistance, and novel therapeutic approaches, highlighting the elusive nature of HDL functionality in disease prevention.

Highlights

• Dr. Dan Rader explains why HDL is often mischaracterized as 'good cholesterol.' 💡
• The role of HDL in reverse cholesterol transport and metabolic health. 🔄
• Intriguing potential of HDL-targeted therapies for cardiovascular and brain health. 🏥
• The ongoing saga and trials around CTEP inhibitors in cardiovascular disease. 🔬
• The underestimated complexity of HDL metabolism compared to other lipoproteins. 🧬

Key Takeaways

• HDL is more complex than just 'good cholesterol'; its biology is intricate and not fully understood. 🤔
• Clinical importance of HDL fractionation is debatable, focusing on other biomarkers might be more beneficial. ⚖️
• Recent trials suggest that merely raising HDL cholesterol doesn't necessarily reduce cardiovascular risk. 🚫
• The therapeutic potential of HDL in neurodegenerative diseases is an emerging area of interest. 🧠
• Understanding HDL function, not just levels, might significantly impact disease prevention strategies. 🔬

Overview

Peter Attia welcomes Dr. Dan Rader to dissect the complexities of high-density lipoproteins (HDL) and their impact on cardiovascular health. Unlike the more straightforward APO B lipoproteins, HDL presents a multifaceted puzzle for researchers. Dan Rader shares insights into the metabolism of HDL and how it differs vastly from LDL, challenging the long-standing narrative around 'good cholesterol.'

The discussion dives into genetic disorders, such as Tangier disease and others, revealing how these rare conditions shaped our understanding of HDL's role in lipid transport and heart disease. Despite hopes pinned on drugs like CTEP inhibitors to manipulate HDL levels positively, trials have consistently shown disappointing results, underscoring the need for alternative therapeutic strategies.

A fascinating segment of the episode covers new research into HDL's function beyond the heart. Dr. Rader explores emerging studies that hint at HDL's potential protective role in neurodegenerative diseases. This new frontier in lipid research could broaden the scope of HDL applications, making functional assays crucial for future clinical practices.

Chapters

• 00:00 - 00:30: Introduction The introduction to the Drive podcast sets the stage for the show's focus on translating longevity science into accessible content. Host Peter Attia aims to provide top-notch health and wellness insights, supported by a skilled team of analysts. The podcast, along with Attia's website and newsletter, targets delivering valuable longevity-related information to the audience. The introduction invites listeners to engage with the content for better health understanding.
• 00:30 - 01:00: Membership Program The chapter introduces a membership program designed to provide more in-depth content for those looking to expand their knowledge in a specific field. It mentions that further details about the benefits of this program will be discussed at the end of the episode, or can be found immediately on a specific website. The episode also features a guest, Dan Rader, a professor at the University of Pennsylvania, specializing in molecular medicine and translational research.
• 01:00 - 02:00: Guest Introduction - Dan Rader, M.D. The chapter introduces Dr. Dan Rader, emphasizing his expertise in lipoprotein metabolism and atherosclerosis, particularly focusing on high-density lipoproteins (HDLs). It highlights his numerous awards and recognitions, including his election to the American Society of Clinical Investigation, the Association of American Physicians, and the National Academy of Medicine. Dr. Rader also holds positions on influential boards such as the International Society of Atherosclerosis, the Board of External Experts at the National Heart, Lung, and Blood Institute, and serves on various advisory boards.
• 02:00 - 03:00: Episode Overview - HDL and Lipoproteins This chapter is centered on high-density lipoproteins (HDLs) as part of a detailed discussion on lipids in clinical research at the NIH. Previously, content has largely been directed towards other lipid-related subjects such as the APO B side, VLDLs, and LP little a, which are related to LDL. However, this marks the first full episode focused exclusively on HDLs. The conversation underscores the importance of HDLs in lipoprotein research, establishing a foundational understanding of their role in health and disease.
• 03:00 - 05:00: Understanding HDL Biology and Complexity This chapter delves into the complexities of HDL (high-density lipoprotein) biology. It challenges the oversimplified notion of HDL as merely 'the good cholesterol,' pointing out that while HDLs are beneficial, it's not just about the cholesterol they carry. The discussion covers various aspects of HDL, including its biological essence, genesis, origin, and metabolism, emphasizing how much is still unknown compared to other cholesterol types. This complexity and the depth of HDL's role in human health highlight why understanding HDL biology is crucial.
• 05:00 - 07:00: Functions and Role of Lipoproteins This chapter discusses the different roles and life cycles of lipoproteins, particularly focusing on HDL and APO b. It highlights the challenges faced in using pharmacological interventions to affect HDL in the treatment of atherosclerosis, contrasted with the significant success achieved in manipulating APO b for cardiovascular disease treatment. The chapter also emphasizes the importance of understanding relevant terminology when discussing these topics.
• 07:00 - 09:00: Comparison of APO B and APO A The chapter delves into the specifics of Apolipoprotein A (APO A) in the context of high-density lipoproteins (HDLs) and makes a clear distinction from Apolipoprotein(a) [APO(a)], clarifying that APO(a) is not equivalent to APO A and relates to Lipoprotein(a) [LP(a)]. The content explores the genesis, structure, and metabolism of HDL, highlighting the differences between HDLs and low-density lipoproteins (LDLs). It also discusses the methodology of HDL measurement, differentiating between HDL cholesterol, APO A concentration, and HDL particle number.
• 09:00 - 12:00: HDL Genesis and Metabolism The chapter challenges the misconception that high High-Density Lipoprotein (HDL) levels automatically translate to cardiovascular disease immunity. The discussion includes an examination of c-tep inhibitors, a drug class aimed at boosting HDL cholesterol levels with the intention of reducing cardiovascular disease risks. The chapter concludes by exploring emerging ideas on the relationship between HDL and neurodegenerative diseases, offering new insights and learning opportunities.
• 12:00 - 15:00: The Role of Apoproteins (APO) The chapter titled 'The Role of Apoproteins (APO)' introduces the topic with a conversation featuring a guest recommended by Tom Dayspring, a respected figure in the field of lipidology. The host expresses keen interest in the subject matter, emphasizing its importance within the broader study of lipidology. Apoproteins (APO) are suggested to be a focal point of this discussion, promising insights into their role and significance in lipid metabolism. The dialogue sets the stage for an in-depth exploration of APOs, aided by the expertise of the guest.
• 15:00 - 17:00: Apo A1 and LCAT's Role in HDL Formation This chapter delves into the role of Apo A1 and LCAT in the process of HDL formation. It highlights the distinction between two broad lipid families: the APO B and the Apo A families. The world of lipidology often emphasizes the APO B family due to our clearer understanding and its direct causal relationship to pathology. In contrast, Apo A1, despite its importance in HDL formation, receives less attention, thus prompting a deeper exploration of its roles and mechanisms.
• 17:00 - 18:00: HDL Particles - Size, Density, and Function The chapter begins with a conversation about lipoproteins, which are complex molecules evolved to transport lipids through the blood. Lipids, being oily substances, do not mix well with water, drawing an analogy to how oil droplets float in water. This foundational explanation is set to provide a backdrop for a deeper discussion on HDL particles.
• 18:00 - 22:00: Comparing Human and Animal Lipoproteins In this chapter, the mechanism by which lipoproteins transport lipids in the blood is discussed. The name 'lipoproteins' itself highlights their function, as they are composed of lipid cores surrounded by proteins. This structure allows them to circulate and be metabolized in the bloodstream efficiently. Additionally, the lipoproteins can bind to specific receptors and have certain proteins and lipids that facilitate their complex transport processes.
• 22:00 - 25:00: Discussion on Evolution and the Need for APO B The chapter titled 'Discussion on Evolution and the Need for APO B' delves into the role and significance of APO B lipoproteins. The discussion highlights that APO B lipoproteins have evolved primarily to transport triglycerides, serving as an energy source. The transportation occurs from the gut to various parts of the body including adipose tissue, muscles, and the heart, as well as from the liver during fasting periods. The chapter underscores the causal relationship between APO B lipoproteins and atherosclerotic diseases.
• 25:00 - 27:00: Nomenclature and Complexity of Lipoproteins The chapter discusses the structure and complexity of lipoproteins, with a focus on high-density lipoproteins (HDL) and their role in cardiovascular health. HDL is characterized by the presence of apoa1 protein, as opposed to other lipoproteins containing apob protein. HDL plays a crucial role in the transport of lipids, particularly cholesterol, and differs from other lipoproteins in its function and structure. The chapter aims to explore the significance of these differences in the context of cardiovascular disease.
• 27:00 - 31:00: HDL Subclasses and Clinical Relevance The chapter titled 'HDL Subclasses and Clinical Relevance' explores the role of lipoproteins as transport vehicles within the blood. It emphasizes the importance of understanding lipoproteins due to their insolubility, in contrast to water-soluble substances like glucose and electrolytes, which easily move through the circulatory system. The chapter aims to highlight the clinical significance of HDL (High-Density Lipoprotein) subclasses and their function in lipid transport and cholesterol management in the circulatory system.
• 31:00 - 34:00: Continued HDL Metabolism and Function The chapter discusses HDL metabolism and function, focusing on triglyceride lipids. It introduces the complexity of the system and emphasizes the need to clearly distinguish between different nomenclatures, particularly between APO a and LP little a, to avoid confusion. The clarification is made that while APO a is discussed, LP little a, which has another APO a little a component, will not be the focus of this discussion.
• 34:00 - 42:00: CTEP Inhibitors and HDL Cholesterol Trials The chapter titled 'CTEP Inhibitors and HDL Cholesterol Trials' discusses the differences in terminology related to protein Apolipoprotein A (APO A). The transcript highlights the importance of distinguishing between 'APO A1', which is the focus of the discussion, and 'lp little a', which is different and not the subject of this conversation.
• 42:00 - 48:00: Pharmacological Interventions and Outcomes The chapter discusses the historical lack of effective public relations in the lipid research community during the 60s, 70s, and 80s, which led to complex and challenging nomenclature. The speaker suggests that with better naming and communication strategies, patients might have had an easier time understanding lipid-related topics. The chapter hints at discussions on different types of APO A proteins.
• 48:00 - 52:00: Niacin's Effect on HDL and Historical Perspective The chapter begins by referencing APO A1 and discusses its significance. It then transitions to a broader look at the APOB proteins, particularly focusing on the two lineages: APO B100 and APO B48. APO B100 is emphasized as the primary focus when discussing APOB, whereas APO B48 is linked to the transportation of chylomicrons from the gut for energy use.
• 52:00 - 57:00: Understanding Reverse Cholesterol Transport (RCT) The chapter titled 'Understanding Reverse Cholesterol Transport (RCT)' discusses the origins and development of high-density lipoprotein (HDL). It explores its formation, evolution, and how it's measured in terms of HDL cholesterol. The complexity of HDL metabolism is highlighted, suggesting it may be more intricate than that of other lipoproteins such as LDLs and IDLs, emphasizing the challenges in understanding HDL despite the speaker's involvement in the APO B community.
• 57:00 - 61:00: Cholesterol Efflux and HDL Function The chapter begins with a focus on the complex topic of cholesterol efflux and HDL function. The speakers acknowledge the challenge of understanding this area due to its intricacies within the lipid field. The discussion starts with a simplistic approach before delving into more details, guided by Peter. APO A1 is introduced as the key protein associated with HDL, compared to apob, hinting at the upcoming detailed exploration of these components.
• 61:00 - 64:00: Advancements in Measuring HDL Function This chapter discusses the differences in apolipoprotein B (APO B) and apolipoprotein A1 (APO A1) and their roles in lipid particles. APO B is present throughout the lifecycle of the particle and is produced by the intestines or liver. It eventually gets absorbed mainly by the liver. APO A1 is also produced by the intestine and liver and acts as a core protein, indicating a parallel in their functions.
• 64:00 - 76:00: Apo E and Neurodegenerative Diseases The chapter titled 'Apo E and Neurodegenerative Diseases' discusses the role of Apolipoprotein E (ApoE) in relation to high-density lipoproteins (HDL) and neurodegenerative diseases. The transcript emphasizes the presence of multiple molecules of ApoE on any given HDL particle, ranging from one to four, or possibly more in certain cases. Additionally, it mentions the dynamic nature of ApoE, indicating that it does not always remain on a single particle but can transfer to other mainly HDL particles or sometimes to other lipoproteins containing ApoE. This transferability and molecular presence of ApoE on HDL have been a significant focus of research in the past decade, offering insights into its function and impact on neurodegenerative conditions.
• 76:00 - 82:00: Conclusion and Future of Lipid Research The chapter discusses the process of HDL (High-Density Lipoprotein) formation, starting with its initial exit from either the intestinal enterocyte or the liver's hepatocyte. It is released into the blood mostly as a free protein. A crucial early step in HDL's formation involves its interaction with a transport protein known as ABC A1. The role of ABC A1 is emphasized as essential in this process, particularly in lipid handling. The chapter aims to address the future implications and direction of lipid research by focusing on these molecular interactions.
• 82:00 - 85:00: Podcast Outro and Membership Benefits The chapter discusses the process of lipids, specifically cholesterol and phospholipids, being exported from the cell and acquired by a newly secreted lipoprotein known as apoa1. This acquisition is crucial for the formation of nascent or early High-Density Lipoprotein (HDL). The chapter hints at further discussion related to genetics, mentioning that humans lacking a specific protein, abca1, are significantly impacted.

240 ‒ The confusion around HDL and its link to cardiovascular disease | Dan Rader, M.D. Transcription

• 00:00 - 00:30 foreign [Music] welcome to the drive podcast I'm your host Peter attia this podcast my website and My Weekly Newsletter all focus on the goal of translating the science of longevity into something accessible for everyone our goal is to provide the best content in health and wellness full stop and we've assembled a great team of analysts to make this happen if you enjoy this podcast we've created a
• 00:30 - 01:00 membership program that brings you far more in-depth content if you want to take your knowledge of the space to the next level at the end of this episode I'll explain what those benefits are or if you want to learn more now head over to Peter attiumd.com forward slash subscribe without further delay here's today's episode I guess this week is Dan Rader Dan is a professor of molecular medicine at the Perlman school of medicine at the University of Pennsylvania where he conducts translational research on
• 01:00 - 01:30 lipoprotein metabolism and atherosclerosis with a particular focus on the metabolism and most importantly function of high density lipoproteins hdls Dan has received numerous Awards and has been elected to the American Society of clinical investigation the association of American Physicians and the National Academy of Medicine he also currently serves on the board of directors of the international Society of atherosclerosis the board of external experts at the national heart lung and Blood Institute and The Advisory board
• 01:30 - 02:00 for the clinical research of the NIH in this episode we focus our entire conversation around high density lipoproteins or hdls now as any listener of this podcast will know we have no shortage of content around lipids and we focus a lot of that energy on the APO b side of the family that is to some extent vldls and of course LP little a which is a subset of LDL however this is the first time we're doing a dedicated podcast on hdls now the reason for that in other words
• 02:00 - 02:30 the reason for that disparity is largely because HDL biology is so much more complex and we know so much less I mean at the highest level I think people generally think of HDL as quote unquote the good cholesterol but you've no doubt heard me rail on the stupidity of such a designation but there is clearly something good about hdls as in the lipoproteins not the cholesterol and in this discussion we really talk about everything from the biology of the HDL it's Genesis its origin its metabolism
• 02:30 - 03:00 its life cycle and of course it's function we also talk about why it has been so complicated to use pharmacologic interventions on the HDL side of the equation to impact atherosclerosis conversely of course it's been the easiest thing I would say in medicine and perhaps the greatest success of modern medicine especially as it comes to cardiovascular disease has been our ability to manipulate the APO b side of the equation as opposed to the APO a side of the equation that's one thing that's going to be important here when we get into the terminology when we talk
• 03:00 - 03:30 about APO a in the context of hdls we're talking about APO a as in a big a which has no bearing whatsoever to APO little a the thing that of course defines an LP literally but I digress that is simply one of the many details we get into so as I said we're going to talk here about the the Genesis of the HDL the structure its metabolism we talk about the differences between hdls ldls the difference between the HDL measurements what exactly is HDL cholesterol versus apoa concentration versus HDL particle
• 03:30 - 04:00 number talk about the idea that having a high HDL means you don't need to worry about cardiovascular disease and how that's obviously going to be bunk I'm just going to let the cat out of the bag on that one we speak about c-tep Inhibitors which are a class of drug that have been repeatedly used to try to increase HDL cholesterol with the hopes that that would reduce cardiovascular disease and finally we end the conversation around some of the new thinking around HDL and neurodegenerative disease something again I learned a lot about so without further delay please enjoy my conversation with Dan Raider
• 04:00 - 04:30 [Music] well Dan thank you so much for making time to join us on the podcast today Tom Day Spring really recommended you highly and anytime Tom Dayspring says to me you should have so and so on the podcast to talk about anything that has to do with lipids I immediately pay attention Tom's an amazing guy now in particular the subject matter I want to explore with you today is probably the area of lipidology that I personally am the
• 04:30 - 05:00 least familiar with and that has to do with kind of one half of the lipid family you know I explain this to patients as they're broadly speaking two families the APO B family and the apoa family we spend obviously so much more time talking about the APO B family based on I think two things one is our clearer understanding of it and two the direct and causal relationship to pathology but I often sort of waffle a bit when I'm talking about the apoa side of the house that's really why I'm
• 05:00 - 05:30 excited to be sitting down with you today but perhaps for the person listening to this who doesn't even understand what A lipoprotein is yet never mind what the two families are that we're talking about can you take it back to the the beginning for where do these things fit into the broader architecture of our existence lipoproteins are these big complexes that really are evolved to transport lipids within the blood you know lipids are like oil they don't mix well with water you know oil droplets float to the top of a puddle we wouldn't be able to
• 05:30 - 06:00 transport lipids in the blood if we hadn't evolved a mechanism to do that and lipoproteins are basically the mechanism to do that as their name suggests they're lipoproteins they have lipid in the core and then they have proteins that dot the surface that allows them to be transported in very complex and sophisticated ways within the bloodstream in terms of how they're metabolized in terms of The receptors they bind to and in terms of the specific proteins and lipids that they
• 06:00 - 06:30 carry you've talked a lot about APO lipoproteins I've listened to several of those podcasts they're really fabulous and of course the APO B lipoproteins really primarily transport or evolve to transport triglycerides as a source of energy you know both from the gut to adipose and muscle and and heart as well as from the liver during times when we're fasting you've talked a lot about that and as you pointed out they are very important in terms of causal relationship to atherosclerotic
• 06:30 - 07:00 cardiovascular disease HDL which we're going to be talking about today is also a lipoprotein it's a very complex lipoprotein it doesn't have this key Protein apob that's what differentiates them that's why we often refer to the APO B containing lipoproteins and then HDL is the other half as you said and HDL really is characterized by a different protein called apoa1 HDL also transports lipids especially cholesterol and some other complex lipids and we'll be getting into that more but essentially lipoproteins are lipid
• 07:00 - 07:30 transport vehicles within the blood and really evolve to do that function a couple things I'll just throw in for folks again maybe new to some of this which is all of the stuff we're talking about is so important in terms of these lipoproteins because unlike glucose electrolytes things that we kind of take for granted that are water soluble we use our circulatory system as the freeway to move these things around and unfortunately as you said because of the insolubility of both cholesterol
• 07:30 - 08:00 triglyceride lipids Etc we have to come up with this more complicated system I think the second thing I'll throw in just for folks because it could get confusing with the nomenclature when you talk about APO a I want to make sure people understand we're not talking about LP little a which has another APO a little a so maybe just clarify for folks the difference between those two because we'll do our best to not talk about APO little a today at all yeah April little a is or LP little a is
• 08:00 - 08:30 really important not the topic of today's discussion I think as Peter already said the main thing to remember is that that a is lowercase whereas the a we're talking about today is uppercase I know it sounds crazy it's just the way things evolved historically but we're talking about a APO a uppercase a and the most important one has a one after it so APO A1 so you're going to hear us refer to APO A1 a lot totally different than the lp little a which is also an
• 08:30 - 09:00 important topic but not for today yeah it's a shame that the lipid Community back in the 60s 70s and 80s didn't hire kind of a PR firm to sort of help with the naming of this stuff because it is hands down some of the most complicated nomenclature and if they realized back then I'm half joking that it wouldn't be a bad idea for patients to actually understand this stuff I think we could have done better okay so you've already alluded to kind of different APO A's and
• 09:00 - 09:30 APO A1 again that's APO capital a dash Roman numeral one is the most important but let's go back even further than that so again not to draw the apobs into this again but we kind of technically now have these two lineages of apobs right we have the APO B100 and virtually all of the time that we say April OB we really mean APO B100 and that's to contrast it with APO b48 the one that you kind of alluded to very briefly as transporting chylomicrons from the gut for the use of energy can you talk a little bit about the or not a little bit
• 09:30 - 10:00 maybe a lot of bit about the Genesis of the high density lipoprotein what is its parent where is it formed and how does it move through its Evolution such that you know when we're measuring HDL cholesterol something we'll talk about in a minute we have a sense of where it came from in the same way that we understand the ldl's idls and ldls with all due respect to the APO B community and I'm part of that Community too I would say the metabolism HDL is perhaps an order of magnitude even more complex
• 10:00 - 10:30 and that's obviously what we're going to be working our way through today so I'll start relatively simplistically and then Peter I know you'll lead me to increasingly more detail about the process and by the way I don't think anyone's going to disagree with that Dan I mean I don't think anybody who's spent even a month modicum of time looking at this literature it is hands down the most confusing stuff in the lipid space again I'll start with APO A1 as the key protein with HDL the analogy is to apob as Peter alluded to
• 10:30 - 11:00 although one big difference is APO b as your listeners know APO B stays with that particle throughout its lifetime so it gets made by the intestines b48 or the liver is B100 it stays with that particle there's one molecule of this huge APO B protein and that it basically then ultimately gets taken up mostly by the liver after its time in the blood APO A1 is also made by the intestine and the liver there's some parallelism there it also is a Core protein essentially of
• 11:00 - 11:30 HDL but unlike April B there are several molecules of apoa1 On Any Given HDL particle we'll probably talk more about that but anywhere from one to four maybe in some cases a little bit more and also apeway1 doesn't stay with the particle it can exchange onto other types of mostly HDL particles but even sometimes onto ape will be containing like lipoproteins what we've really learned in the last decade or so is that apoa1 is put into
• 11:30 - 12:00 the blood by either the intestinal enterocyte or the hepatocyte in the liver as more or less a free protein so it's secreted as a protein one of the first steps that has to happen for HDL to be formed is that HDL once it comes out of the cell engages with a key transport protein called ABC A1 and Peter stop me if I'm already getting too detailed ABC A1 we'll come back to that which its role abca1's role is to take lipid
• 12:00 - 12:30 cholesterol and other types of lipids called phospholipids from the cell and Export them to the newly secreted apoa1 so apoa1 has to acquire lipid particularly phospholipid and cholesterol soon after it's been secreted in order for the so-called nascent or early HDL to start forming we'll come back to this when we talk about genetics but we know this because humans that lack abca1 have virtually
• 12:30 - 13:00 undetectable HDL and that is because they cannot they make plenty of apoa1 but they cannot protect that apoa1 with lipid once it's secreted and it goes out like a rocket from the blood basically can't almost can't measure it in the blood so that's the first step in terms of HDL biogenesis if you will what other phenotype do those patients have so in the absence of cholesterol accumulating in what would be an HDL does it end up where more of it ends up in the LDL or
• 13:00 - 13:30 back in the liver where does it go this is the value of studying these very rare human genetic disorders it just tells us a lot about what specific proteins or genes are doing this disorder which we can talk about the history it's a fascinating history it's called Tangier disease it's named for a small flat bizarre island in the middle of the Chesapeake Bay where the first patient was discovered this disorder is primarily associated with accumulation
• 13:30 - 14:00 of cholesterol in macrophages throughout the body so tonsils spleen places where there are a lot of macrophages the cholesterol really builds up and they have huge sort of orange colored tonsils they have big spleens that sometimes rupture they have big livers because there are a lot of macrophages and macrophage-like cells in the liver and they also have some neurologic type issues especially neuropathy which maybe we'll leave to later when we start talking about HDL in its relationship to the nervous system they may or may not
• 14:00 - 14:30 have some increased risk of atherosclerotic cardiovascular disease but as we'll talk about that relationship between HDL and atherosclerosis is quite complex this disorder has helped to inform that a little bit another sort of structural question Dan if you were to take a quasi-mature garden variety HDL particle and again it's more complicated there because of what we're talking about and put it next to a comparable LDL particle what's the difference in size and can you explain a little bit why they come
• 14:30 - 15:00 up with this different name of High versus low density What specifically is that referring to that's a great question again this is a historical artifact of how lipoproteins were discovered and named first of all hdls are much smaller I would say you know in the neighborhood of one-fifth to one tenth the size of an LDL and of course much yet smaller than triglyceride Rich lipoproteins you know lipoproteins have lipid as I mentioned earlier lipid floats so lipids create buoyancy to particles and the way lipoproteins were
• 15:00 - 15:30 discovered is that when you subject plasma to spinning the lipoproteins spin to the top and they spin to the top at different rates under different forces the low density lipoproteins have more lipid or bigger more lipid they spin to the top more easily the high density lipoproteins still have lipid they do spin but they don't spin quite as quickly or easily so they're higher density than the low and then in another artifact of sort of the history Peter
• 15:30 - 16:00 after low density was discovered something even lighter that spun up even more easily was discovered and of course if low was already taken so that had to be called very low and so there's the very low density lipoproteins that you've also talked about at length and then finally the chylomicrons the huge ones that come from the intestine they're just so light and so buoyant that instead of calling them very very very low they were just given the name kylo microns how long does an HDL particle last and
• 16:00 - 16:30 does it mean the same thing given that it's transferring its apoa in a way that makes it a little different from as you said the way the vldl to IDL to LDL always stay with one lipoprotein apob that allows us to kind of track its life before we get into kind of how HDL is removed from the blood could I take a little bit more time to explain what happens after that absolutely apoa1 quote unquote nascent HDL particle gets formed because there's actually a bunch
• 16:30 - 17:00 of stuff that has to happen first before we start talking about how the HDL then gets removed from the blood so the apeway one or the what we call the nascent HDL has you know eight way one has phospholipids and it has what I'm going to call free cholesterol and this is a concept that you may or may not have addressed before I can't remember which is cholesterol itself as a molecule can have a fatty acid attached to it when you attach a fatty acid to a hydroxyl moiety on the cholesterol molecule you create what we call a
• 17:00 - 17:30 cholesterol Ester and the cholesterol Ester is even more hydrophobic or oily than the free cholesterol because it has this additional fatty acid sticking off it which is obviously oil it's absolutely critical for HDL for the HDL maturation process to have this fatty acid attached to the cholesterol after the nascent HDL has been formed and there's another key enzyme that is responsible for that so-called lecithin cholesterol acyl
• 17:30 - 18:00 transferase it's the last time I'm going to say that I'm just going to call it lcat that's its nickname lcat lcat so lcat rides on the HDL particle on that nascent particle it takes a fatty acid from one of the phospholipids on the particle and it transfers that fatty acid to the cholesterol and creates the cholesterol Ester remember that cholesterol Ester is more oily it actually then moves to sort of the center of the particle because it wants to be by itself and not
• 18:00 - 18:30 interacting with the water and it starts to form the core of the HDL particle so the core of the mature what I'll call the mature HCL particle is basically cholesterol Esters that are entirely dependent on lcat for their formation another rare condition are people who lack lcat genetically and as you might maybe expect from what I just said people who lack lcat who can't do that process of esterifying the cholesterol have extremely low levels of HDL not quite as low as Tanger disease
• 18:30 - 19:00 but very low and simply can't form the mature HDL particles that we see in most people so again we learn very important things about the key role of that enzyme that ultimately leads to the mature particle that then is really what we're measuring as HDL cholesterol in people is this mature HDL particle where most of the cholesterol we're measuring is the cholesterol Ester in the core just to make sure we're clear on semantics when you say that those folks have very low HDL you mean low HDL cholesterol or
• 19:00 - 19:30 a low concentration of APO A1 or any of the apoas they have low HDL cholesterol so again Tangier disease HDL cholesterol is one virtually undetectable lcat deficiency HDL cholesterol is 10. also as we'll talk about quite low compared to normal they also have low apoa1 levels and part of that is because part of the metabolism of APO A1 which is where you were going is that it's affected by the
• 19:30 - 20:00 mature HDL and the cholesterol and the core so when you don't make that cholesterol Ester that APO A1 is much more rapidly removed from the blood it's not the normal metabolism and it basically the kidney sees that APO A1 which doesn't have much cholesterol on it and actually filters it and degrades it not surprisingly the biggest issue without cat deficient patients is that get renal disease that is serious Progressive chronic kidney disease in
• 20:00 - 20:30 these patients that leads usually to kidney transplant related to something around the lipid metabolism in the kidney as a result of the lack of lcat activity and esterification of cholesterol before we go deeper on this I just want to ask if there are any insights we have or how parallel is this system in other mammals whether it be primates you know dogs mice Etc because obviously a lot of these animals have a very different apob side of the equation I'm curious as to how similar they are
• 20:30 - 21:00 on this front no that's a great question eight boy one is pretty highly conserved among certainly among mammals in many lower level mammals the primary lipoprotein is HDL that clearly includes apoa1 I'll just take mice obviously a major model system for human for biomedical research mice I'd say 90 percent of cholesterol in the blood of mice is in HDL even more than 90 in a normal mouse that is the primary lipoprotein in mice it's true for dogs
• 21:00 - 21:30 it's true for really all mammalian species I mean once you start getting below mammals things change a little bit in terms of the lipoprotein metabolism probably we won't get into that today but there's even HDL type particles in much lower species leading to one of the kind of thoughts that HDL is kind of like the primordial lipoprotein and that the APO B system kind of evolved subsequently but that HDL probably very early evolved as a
• 21:30 - 22:00 transport mechanism for lipids within circulatory systems in lower level species you know this to me is one of the most interesting kind of teleologic Slash evolutionary questions which is was God just pissed off at us and is that why we as humans have apob because I can't I've never really heard a convincing explanation for why humans have apob when it seems that every other species gets away without it right as you said I mean if a mouse or a primate or a dog
• 22:00 - 22:30 who clearly have similar energetic requirements can use their APO A's I.E hdls for lipid transport and energy mobilization why did we need to evolve with this particle that in the short term really doesn't cause us any trouble of course but long enough it doesn't and so you know one answer might simply be that Evolution had no concern for the longevity of our species that's for sure pretty true but there is some other
• 22:30 - 23:00 short-term benefit from APO B that maybe outweighs the long-term deaths that it brings our species via ascvd I do want to be clear mice dogs pigs rabbits they all make APO B in both the gut and the liver so it's not that these species don't have apob the difference is in terms of looking at the steady state plasma levels is that their APO B system is just really markedly revved up they take care of their business they just must clear it out and it serves a
• 23:00 - 23:30 similar role you know in terms of transporting triglycerides as a source of energy to tissues in the body that need energy and to adipose tissue for storing it it's just that the rate at which they do that is much more efficient whereas in humans for reasons we could talk about but aren't totally clear but certainly have to do partly with our lifestyle humans are not nearly as efficient at clearing the APO B containing lipoproteins and they hang around especially as LDL as a byproduct of this metabolism in a way that then
• 23:30 - 24:00 ultimately leads to of course atherosclerotic vascular disease we do need able be honestly mammals evolved APO B because one we have to be able to efficiently capture fats in the diet for energy purposes and very efficiently that's what the chylomicrons allows to do and during fasting which of course in evolution sometimes lasted a long time we have to be very parsimonious about parceling out that available fat we have in our adipose stores back out to heart
• 24:00 - 24:30 and muscle to be able to have as a source of energy that's what April B100 in the liver does we need these especially in evolution in the latter we need it very substantially but now unfortunately in the modern times the able B system is mostly a problem not something we need and I think the way you stated it earlier is obviously more accurate and perhaps I want to just make sure I'm restating it without being quite as tongue-in-cheek it's really not that we don't need APO B it's that we could be clearing it at a much greater and more efficient rate than we are and
• 24:30 - 25:00 we could more mimic primates and other men animals and walk around with an apob concentration of call it 20 milligrams per deciliter instead of 100 milligrams per deciliter a five-fold difference which is about that's the difference between getting atherosclerosis In Our Lifetime and never getting atherosclerosis in our lifetime I agree with that and that's the interesting thing because even absent kind of the quote-unquote lifestyle things that will raise APO B it just occurs with aging
• 25:00 - 25:30 you know Peter Libby has written about this very eloquently and children neonates have apob concentrations that are just like those of these other animals yeah and all things equal as we age APO B just goes up that concentration goes up as you say we're less efficient in the way we clear apob from circulation anyway it's a fascinating topic and it's I know not what we're going to talk about today because it's one of speculation and we could speculate but there are actually lots of things today that we don't have to speculate about as it comes to apoa
• 25:30 - 26:00 and HDL I want to go back to kind of the nomenclature a little bit because I know I'm still kind of confused used on some of this and I think it's going to be a little challenging because we're sometimes talking about Roman numerals and we're sometimes talking about numbers but is there just an APO a one and two in the Roman numeral lipoprotein April lipoprotein cover no so it goes to two three two other apoas that at least we know about or we talk about are APO A4 and APO A5 don't ask me what happened
• 26:00 - 26:30 to APO A3 that's a mystery I've never I've been able to solve okay but uh anyway it's another one of those eight way four we don't really know what it does APO A5 I can't remember if you've talked about but April A5 has a very important role in stimulating lipoprotein lipase and in the metabolism of triglyceride Rich lipoproteins it rides on HDL but it also rides on triglyceride rich lipoproteins and people who lack April A5 have really
• 26:30 - 27:00 high triglycerides and are also at Major risk for atherosclerotic vascular disease so anyway now again maybe not the topic for today but it does illustrate one point Peter maybe that I'll make which is that HDL as a molecule As A lipoprotein I think of as a platform it's a platform for all sorts of proteins and lipids that get transported by HDL in the blood and then transfer off HDL to other things to April B containing lipoproteins so my
• 27:00 - 27:30 example of April A5 it's named APO a a because it was discovered on HDL but its primary role in metabolism is triglyceride Rich lipoprotein metabolism apoa5 is basically kept within the blood and stored if you will on HDL but then when we eat a fatty meal it transfers off to the triglyceride rich lipoproteins and it serves a role of promoting the hydrolysis of the triglycerides so I think that's a general concept for HDL that maybe we'll keep coming back to is this platform for
• 27:30 - 28:00 all sorts of things that are doing different things that involve not only lipid metabolism but host defense and other things that it evolved to do as a platform for transporting things within the blood which I think explains at least in part the complexity of this system is it's much more Dynamic than what we see on the APO b side the APO b side as you said it's sort of it's a very monogamous relationship right I mean you you sort of get your APO B in the liver and it's
• 28:00 - 28:30 with you for life and you're not swapping you're not trading you're not increasing or decreasing you're just marching through life and the HDL is maybe the monogamy wasn't the best example because now I don't know what to come up with here because it's not just polygamy it's even more complicated than that it's as you said it's swapping it's moving things around it's carrying things that it doesn't really use but loaning them out it is indeed a complicated system the next thing that seems to add a lot of confusion at least to me is some of the nomenclature around the
• 28:30 - 29:00 numbering of the HDL particles and I bring this up in part because various commercial Labs you know someone listening to this goes out and gets a really fancy fancy blood test we use Boston Heart Labs with our patients I know that this is you know something you see with a number of other labs it might say things like hdl1 hdl2 hdl3 what's the relationship between that nomenclature and the APO A1 APO A2 APO A4 Etc this is ridiculously complex the short
• 29:00 - 29:30 answer to your question is actually believe it or not there's no relationship so the numbering of the APO lipoproteins or the apoa lipoproteins one two four five is totally independent of the numbering of the HDL particles like especially hdl2 and hdl3 which are the classic two main quote subclasses of HDL these are different sizes and different densities of HDL that again were isolated by centrifugation and by their flotation properties hdl2 is
• 29:30 - 30:00 bigger hd03 is a little smaller hdl2 has mostly four molecules of apoa1 hdl3 has mostly three molecules of APO A1 but those threes don't have anything to do with each other and then to make things more complicated there are other ways of sub-fractionating lipoproteins and I know you've discussed like the NMR type of methodology that don't use hdl2 and hdl3 which frankly is a little outmoded now but use things like very large large HDL large HDL medium HDL small HDL very
• 30:00 - 30:30 small HDL HDL certainly comes in a whole series of sizes and densities that can be isolated by these different methodologies there's been a cottage industry as you know Peter of trying to relate these different fractions of HDL to cardiovascular risk in a way that might give us some advantages in terms of trying to predict risk we can come back to that but I would say in general I'm not very compelled that
• 30:30 - 31:00 fractionating hdls gives much clinically valuable information that allows us to predict risk in contrast I just want to say in contrast to the April B contained lipoproteins where you know whether it's apobee or whether the but I think the smaller denser LDL particles do have a relationship to increased risk as you've discussed in the past but I think the HDL fractionation is fascinating for understanding HCL biology and metabolism them but is relatively unimportant from
• 31:00 - 31:30 a clinical relevance standpoint I'm actually glad to hear you say that because I was wondering if I need to be changing our clinical practice in about 2016 we basically stopped paying attention to any of the HDL fractionation metrics and really it you know had to go out of our way to make sure that the lab was not running those because you know in some areas we're running complicated labs and we were sort of saying look we don't want any of this stuff a we don't
• 31:30 - 32:00 want the additional cost of it but more importantly we don't think it's clinically actionable we still get Labs from other doctors who might have seen our patients in the past and they're chock-full of these things to which I don't know what to do with them but while we're on this topic of hdl's fractionation unless you want to ask me another question no no I wonder if I could use this as a springboard to continuing this complex Saga of the metabolism of hdls once they're formed and once they have cholesterol Ester and
• 32:00 - 32:30 the reason we have this whole sort of set of different size and density hdls is because of the complex metabolism that occurs on the hdls once they're in the blood once they've kind of made been made mature hdls I want to give you maybe a couple examples of that one is that hdls are acted upon by so-called lipases and you've talked a lot about lipoprotein lipase that's critically important for triglyceride metabolism
• 32:30 - 33:00 and energy metabolism lipoprotein lipase has two other very close cousins that I don't think you've talked nearly as much about appropriately because they're more HDL related one is called quote hepatic lipase and what is called quote endothelialipase we actually first reported a long time ago endothelipase as a member of this family so both of these lipases they're made in different places as their name suggests but both of them fundamentally chew on HDL specifically the phospholipids on HDL
• 33:00 - 33:30 and result in modification of the phospholipid composition of the HCL particle in a way that does different things it certainly changes the sizes of the hdls and they contribute to this distribution of different sizes it changes the protein composition of the hdls in ways that we don't fully understand and almost certainly has other important biological effects that we don't fully understand but of course these evolve for some reason one of which I'm going to get back to later when we talk about the central nervous
• 33:30 - 34:00 system so that's one lipases are really critical for HDL metabolism there's also this protein that I know you've had some discussion about cholesterol Ester transfer protein happy to go into more detail and I'm sure we will because it's very relevant to HDL but just for the metabolism part of it this so-called cetp cholesterol transfer protein essentially transfers cholesterol Esters between April B containing lipoproteins in HDL and it's a major modifier of the HDL particle in
• 34:00 - 34:30 terms of its size and composition we know this because people who lack CTP have hugely elevated HDL cholesterol levels big time like over a hundred that really told us that cholesterol Ester transfer protein siphons cholesterol out of HDL and when you don't have it you have a lot more cholesterol in HDL and just point back to our previous discussion of mice mice don't have CTP so among the differences one of the
• 34:30 - 35:00 things is that mice have a lot more HDL cholesterol relative date would be because they lack this CTP protein I mean I know we're going to come back to this but I just I worry that for the listener this would be an opportunity missed if we don't dive into ctep a little bit because of the following if we take a step back a listener is going to be saying Peter Dan what the hell are you guys talking about like I am so lost the only thing I know is when I go to the doctor
• 35:00 - 35:30 the doctor says my good cholesterol is high I'm in good shape so let's do this let's hit pause for one sec and acknowledge that a standard lipid panel spits out a bunch of numbers total cholesterol LDL cholesterol HDL cholesterol and if you're lucky vldl cholesterol non-hdl cholesterol and triglycerides that's basically the standard metric if the lab is competent and they're using direct measurements your HDL cholesterol LDL cholesterol and
• 35:30 - 36:00 vldl cholesterol should sum to your total cholesterol and of course your non-hdl cholesterol should be the same number as your total cholesterol less your HDL cholesterol want to pause and also insert that with nomenclature HDL is not a laboratory metric it is a lipoprotein the laboratory metric is HDL cholesterol hdlc or if using NMR hdlp htl particle number or apoa1 an analogy
• 36:00 - 36:30 to measuring April B exactly the units that you've been throwing around of course are the HDL cholesterol a moment ago you said hey people with who are deficient in ctep could have hdls over 100 of course that means HDL cholesterol over 100 milligrams per deciliter now there is an observation that goes back probably to the late 70s right I mean it probably goes back to late 70s early 80s which is in some of the earliest Framingham cohorts which observed the risk of ascvd in five cities we don't
• 36:30 - 37:00 need to go into what Framingham did in the first cohort but what came out of that was higher HDL cholesterol was better than lower HDL cholesterol in fact that was four times greater if my memory serves correctly as a predictor of ascvd than high LDL cholesterol was a negative predictor am I remembering that correctly yeah that's about right yep so it's by now we're talking about 82 83 84
• 37:00 - 37:30 this has been a long time since I've looked at this stuff but it emerges that hey High HDL cholesterol seems to be positively associated with outcomes and obviously that's a big part of why HDL cholesterol became known as good cholesterol and LDL cholesterol became known as bad cholesterol we'll obviously talk about why those terms are inaccurate but it wasn't long until companies drug companies were saying hey wait a minute we know that if ctep is inhibited this
• 37:30 - 38:00 enzyme is inhibited HDL cholesterol goes up that must be a good thing right that led directly from this observation I mentioned that people who lack CTP genetically have these hugely elevated levels of HDL one directly from the other well gosh that must mean that if we could pharmacologically inhibit CTP it would be a way to raise HDL and of course as you know that absolutely turned out to be the case but the story
• 38:00 - 38:30 is goes beyond that so the first company to do this was Pfizer right wasn't the first ctep inhibitor the first CTP inhibitor torsatropy was from Pfizer correct and that was you could take a skeptical view of the trial which was Lipitor was about to go off patent and so they came up with a trial that was Lipitor by itself versus Lipitor combined with the ctep inhibitor and I remember actually this was probably early 2000s right thinking oh this is
• 38:30 - 39:00 super I mean this is you know back when I was in my surgical residency so I was only tangentially interested in this right it wasn't my field but interesting in that I knew my family history for ascvd was high so I was paying attention and I remember thinking well God this has got to be great right you got one drug that's going to lower ldlc one that's going to raise hdlc this is a can't miss drug and then in September of 2006 lo and behold not only did it not get better it was slightly worse right yeah bombshell so first I want to emphasize the genetics did predict what
• 39:00 - 39:30 happened that is pharmacologic inhibition of CTP is extraordinarily effective at raising HDL a lot in fact putting people kind of over a hundred HDL cholesterol like the folks who lack CTP but you're absolutely right there a lot of excitement about that a lot of excitement about HCL is the good cholesterol and that trial the first of several with different CTP Inhibitors not only didn't show benefit but showed an actual adverse effect now it has to be said that in retrospect we're pretty
• 39:30 - 40:00 sure that adverse effect more people literally more people died that adverse effect was due to off-target effects of the drug not due to CTP inhibition itself so that drug of course was discarded but it didn't kill the field because the idea was well that was just a bad drug let's get a clean CTP inhibitor and see what that really does I don't know if you want to ask me questions or I can continue the story yeah let's go down that path because it's still a little it got progressively
• 40:00 - 40:30 less murky as time went on but let's go down the path of the evolution of ctep Inhibitors which let's be honest it's for what we're almost 50 well actually 16 years post the halting of that trial and the discarding of that drug and we still don't have a c-tep inhibitor on the market right we don't there is still a c2b inhibitor that's in development which I'll get to but there is certainly not one on the market as you know Peter and certainly probably many of our
• 40:30 - 41:00 listeners do three additional CTP inhibitors were then taken into late stage clinical development including large cardiovascular outcome trials to summarize the results of that one of them was just flat didn't do anything didn't hurt people but didn't help a second one was stopped early because it really didn't look like it was doing anything helping and the third one was followed through and did show about a disappointing nine percent reduction in
• 41:00 - 41:30 cardiovascular events but I also want to point out that it lowered LDL and April B pretty well also nine percent given that you also lowered LDL and APO B was not exactly exciting and that drug was not taken further in terms of approval I have to say one other thing that's just fascinating for sort of our field and maybe in general one of these drugs dalceptropip that failed in its clinical trial a detailed genetic study was done post hoc and there were individuals who were
• 41:30 - 42:00 found to have a particular genetic variant that looked like on post-hoc analysis that group actually benefited from the drug and that led to a subsequent attempt to do another trial focused specifically on people of that genotype with this CTP inhibitor which was just reported out really within the last year as a negative trial that's ATP actually had two different trials one and kind of a very focused Precision medicine way but
• 42:00 - 42:30 it still didn't produce any benefit this has been a long Saga of using CTP inhibition to raise HDL as a way to reduce risk and as we're going to be talking about more it really is one of the key planks that has led to I think what is now Rock Solid which is HDL cholesterol itself the HDL cholesterol itself is not directly and causally protective against atherosclerotic
• 42:30 - 43:00 cardiovascular disease there's a lot of nuances there which we'll come back to but I feel pretty confident making that statement and I just think this is a great opportunity to also talk about why it's so important to have hard outcome trials in the field of cardiovascular medicine I think it's true in all medicine but let's go back and think about the first lipid lowering drug introduced in the United States in God about 1950 right maybe 1959 something like that right so trypanarol which I
• 43:00 - 43:30 can never remember the name of the enzyme but it's the enzyme that converts does mosterol to cholesterol in the cholesterol synthetic pathway believe it or not this is a sign of my aging Dan I used to know the names of these enzymes it was like and it's not Delta 24 desaturates but it's a cousin or derivativism right but anyway so you had this drug triparanol that inhibited that enzyme and lo and behold it lowered cholesterol now this was for the listener this is back in the day before we knew anything about the sub-fractions of cholesterol so we just knew from some
• 43:30 - 44:00 of the early work of Ansel keys but if you looked at very very high levels of total cholesterol and compared that to people who had very very low levels of total cholesterol there was a difference in outcome cardiovascular outcomes this was an observed finding there was no intervention to test that so this drug came along and it really lowered total cholesterol and it likely would have been lowering LDL cholesterol and apob it basically got approved on the basis of that without of course the hard outcome so it gets approved it goes into
• 44:00 - 44:30 circulation and it's really only after it was approved gosh probably what eight to ten years later that they had enough post surveillance data to say you know what this drug is lowering cholesterol all right but it's actually increasing mortality cardiovascular mortality drug was pulled off the market I don't know what is known about the why but I know Tom Dayspring and I have speculated that it was probably the Des moistural Spike that was causing the problem so you
• 44:30 - 45:00 might have been trading one problem for a worse problem are you familiar with that drug or that story only peripherally but of course there's been a ton of research in desmaster all really over the last several years we now based on that that the plausibility of the fact that the adverse effects were related to increasing this nostril I think is quite real that very well may be the explanation by the way this is a totally tangent off-topic point but it's become quite in Vogue to use clomiphene
• 45:00 - 45:30 or Clomid for testosterone replacement in men and the reason for it is a it's quite effective so if you give clomiphene you are telling the pituitary to make a lot of LH and FSH which of course is telling the testes to make a lot of testosterone this would certainly in the short term have the advantage of preserving testicular function unlike giving exogenous testosterone which suppresses testicular function and I think for short-term use it probably
• 45:30 - 46:00 isn't a bad thing it's an off-label use of course for clomiphene and we used to do it for this purpose right so if a guy was still considering reproduction or you know we were considering this a bridge treatment between testosterone we would use it but because we always measure Des moisturol lethostarol composterol cytoster all these sterols when we measure our patients cholesterol levels we noticed how high the Des moistural levels were getting in those patients and we figured out it was pretty quickly
• 46:00 - 46:30 it was the Clomid that was doing this and it would reverse but it could take a year to return Des mocerol levels to normal after you stopped the Clomid so about four years ago once we put two and two together we stopped using Clomid but it's interesting to me that the use of that hormone has gone through the roof there are now like Clomid clinics opening up and I don't understand why someone and we've done a lit search I don't understand we just need to write this up I think at some point yeah it's fascinating because I don't understand
• 46:30 - 47:00 why someone hasn't put the two and two together especially long-term use again I don't think using Clomid for a couple of years is going to be problematic and I certainly don't think it's problematic for women using it for IVF when I think about a guy being on this for 10 years and I'm talking desmaster all levels you know going up by 20-fold that would be concerning you know we went back and tried to see if we could find out how high the Des moistura levels were in the triparanol trial not trials but in the
• 47:00 - 47:30 you know the levels that if anybody had pulled serum or saved serum from those obvious we couldn't find it so we don't really know how high it was but the Assumption has to be that that drug and clomiphene both interfere with the same enzyme really fascinating I would encourage you to write that up so what's the point of that whole long-winded Story the point of that long-winded story is things can make a lot of sense until they don't right that's for sure before we leave CTB inhibition though I do want to just remind your listeners that there is still one CTP inhibitor
• 47:30 - 48:00 obisattropin that is still in clinical development what differentiates it it's much more effective at lowering LDL and apob we now no longer think that raising HDL cholesterol with CTP inhibition is going to help you we don't think it hurts you but we don't think it's going to help you but we do think that there's still merit of course we know there's Merit to raising LDL cholesterol and apob you mean lowering I'm sorry rate lowering perhaps this CTP inhibitor could be part of the armamentarium to do that so we'll see
• 48:00 - 48:30 stay tuned now Dan Maybe This Was Naive of me but after the third failure of the ctep inhibitor my very crude interpretation is not unique I'm sure a lot of people have speculated this is that if at least part of the benefit of HDL involves stuff we're going to talk about right delibidation reverse cholesterol transport all of those things and you slap a c-tep inhibitor on one of those particles
• 48:30 - 49:00 thereby making it harder for the particle to efflux its cholesterol to get rid of its cholesterol which is why you now measure much higher HDL cholesterol which on the surface looks good that could actually be problematic in other words if you see a lot of people in a room it might be tempting to conclude that there's something awesome going on in that room but what you don't know if you can't measure all the ins and outs is it might be that those people are all stuck in the room because the door is locked I know that's a bit of a crude analogy but is there any Merit to that sort of
• 49:00 - 49:30 thinking around the different ways in which one might boost HDL cholesterol and how some of those could actually be deleterious if they prevent function there absolutely is but I think it's probably not relevant to CTP for reasons we can return to but it is relevant to another protein that I think now is a good time to introduce which is another key protein a receptor that is basically the major HDL receptor the essentially the equivalent of the ldar receptor but for HDL and it's known as srb1
• 49:30 - 50:00 another unfortunate nomenclature but srb1 is a receptor that basically is on a lot of cells but the liver is the most important with regard to HDL and it essentially binds the HDL particle basically sucks the cholesterol Ester out of the HDL particle and then releases the cholesterol depleted HDL back into the circulation to go back around and do whatever it's doing so the analogy I like to use Peter is that of garbage trucks so a very simplistic view
• 50:00 - 50:30 of HDL which we're going to return to because it's much more nuanced is that HDL to a certain extent functions like garbage trucks that are picking up things trash in places where you don't want it and returning it to the liver dumping it off via sob1 and then going back now empty to do more of its role again it's more complicated than that but that's an analogy so this brings me back to srb1 so there are humans who lack srb1 what
• 50:30 - 51:00 do you think the problem is very high they have very high hdls they have very high age deals because they can't unload the dump trucks but they actually have increased risk of heart disease because they are not efficiently unloading that HDL so very similar to your analogy of the locked room you're not clearing the HDL and doing that normal process of recycling the trucks back to the periphery to do what they need to do and so that's I think our best example of this concept
• 51:00 - 51:30 of constipation of the system leading to high HDL but paradoxically to increase risk and of course the analogy would be that not the analogy but the interpretation of that would be you would never want to develop an srb1 inhibitor yes it would raise HDL quite a lot but it wouldn't protect against heart disease and probably would hurt people yeah I remember the first time Tom shared a case study with me of a patient with presumably defective not
• 51:30 - 52:00 necessarily completely absent but uh srb1 and this was you know one of those things where you could tell just reading the journal it must have been 40 years old but her LDL cholesterol was you know whatever it was 100 milligrams per deciliter her HDL cholesterol was like 150 milligrams per deciliter so she had quote unquote high cholesterol but initially you know people assumed it was not of concern because the fraction that was HDL cholesterol was what was contributing to it and of course on further exam I mean she had very very Advanced atherosclerosis for a woman her
• 52:00 - 52:30 age yep exactly we don't see this often I can tell you that I have not yet seen a case of that now admittedly my practice is not large but we're certainly looking for it when we see people with high HDL cholesterol typically you know north of 90. I guess we should talk about this as well but we can do that in a moment after this question which is why is there a sex difference between these two because there is quite a significant sex difference between men and women in terms of HDL cholesterol but at what
• 52:30 - 53:00 point Dan as a clinician do you start to worry about that and if there are doctors or patients listening to this when would you recommend that somebody go and get checked out for a genetic deficiency there S31 deficiency is not common I completely agree with you a huge project we've had for a long time now is essentially collecting people or consenting people with extreme High HDL with the goal of trying to find what the underlying genetic cause is and I will tell you that that's how we found a few of these srb1 folks but most of them
• 53:00 - 53:30 don't have any identifiable Gene that we can point to and say Here's the Smoking Gun here's why your HDL is high HCL is very heritable meaning that there's a lot of genetic determinants of HCL but it's more about so-called polygenic inheritance where multiple different genes including srb1 but not major genetic defects just sort of more common variants but many others like some of the things we've been talking about including as CTP and abca1 all contribute to the heritability of the HDL cholesterol but to get back to the clinical implications
• 53:30 - 54:00 you know my view at this point we can talk more about the data it's pretty clear that you know High HDL is not uniformly associated with protection and there's certain circumstances where that's true especially if it's extremely high perhaps we'll get back to this but there's a fair amount of evidence now including a recent paper that individuals of African ancestry who tend to have iron hdls anyway that the high hdls are not as protective or maybe not even HCL is that well associated with risk so my clinical advice to anyone
• 54:00 - 54:30 with high HDL is not you know go get yourself sequenced to find out if you're deficient in srb1 the odds of that are extremely low but never use a high HDL as a reason for not using a Statin or some other LDL lowering or preventive therapy that is you should never be dissuaded from doing what you would have otherwise done in that patient just because their HDL is high does that make sense it absolutely makes sense and I have a very short paragraph in my book
• 54:30 - 55:00 that'll be coming out in a while where I cite two mendelian randomizations that you know really look at this in some detail I think I've explained mendelian randomization before in the podcast but it's always worth I think a short explanation again in case you haven't heard it this is basically a technique where you look for genes that impact traits that you are interested in so in this case because as you pointed out HDL
• 55:00 - 55:30 is very genetic that means that there are sets of genes that we would identify that predispose people to having very high versus very low HDL cholesterol and because those genes are randomly occurring you can look at that as though it's a natural experiment and you can look at based on the natural occurring spreading or scattering of those genes how our outcomes affected and it turns out that low HDL cholesterol is not
• 55:30 - 56:00 causally linked to atherosclerosis and high HDL cholesterol genetically high is not causally linked to protection from ascvd so I think those are very important findings and I think it speaks to why as you say you can't use high HDL cholesterol as a reason to not treat in the presence of other risk factors I completely agree it's interesting though that that persists isn't it I do find this to be probably top three most
• 56:00 - 56:30 vexing discussions I have with other Physicians which is I know is LDL cholesterol is 140 milligrams per deciliter but God I mean as HDL is is 80 I mean you know his ratio I mean that's when they say the ratio of total cholesterol to HDL or LDL to HDL is such and such and therefore I don't need to treat I mean I it makes me wish I had hair to pull out you're absolutely right and I'll just reiterate High HDL is never a reason not to treat someone who would have otherwise married a treatment I do want
• 56:30 - 57:00 to make clear though there are lots of people who are on the fence about whether to start a Statin who have ldls that are kind of borderline or even not that terribly high but and of course we look at the whole patient we look at the risks we look at their calculated risk other risk factors but I'll just say that a low HDL in the setting of someone who you're generally on the fence about treating perhaps could contribute to tilting toward yes I'm going to treat this person in other words a low HDL at least
• 57:00 - 57:30 in most populations again I think individuals of African ancestry perhaps we have to be a little bit more careful about using HDL as a predictor well maybe we'll come back to that otherwise I think a low HDL can be used not absolutely but relatively to tilt toward being more aggressive but only in the context of the overall risk profile and obviously part of that Dan has to do with the relationship between low HDL cholesterol if my memory serves me correctly it's the hdl2 fraction and the
• 57:30 - 58:00 association with that in insulin resistance so there's no question that a phenotype and as you point out and we should come back to this we don't even do this calculation for African-American patients because we've long observed it's not helpful but in non-african-american patients the ratio of triglyceride to HDL cholesterol when both are in milligrams per deciliter you know is reasonably associated with insulin resistance and the higher that ratio the more insulin resistant they are and obviously that ratio is driven
• 58:00 - 58:30 up by an increase in triglycerides and a reduction in HCL cholesterol why is it that I mean we spend hours on this podcast talking about why insulin resistance would lead to or be associated with high triglycerides we haven't done the opposite or the reverse of that what is it about IR that drives down hdl2 I'll just say the first though that one of the other analogies I like to make is that HDL cholesterol while not causally related to disease is sort of like an hba1c
• 58:30 - 59:00 for cardiovascular risk factors it's an integrator of information related to insulin resistance related to triglycerides related to inflammation that in one number in most people when it's low it's telling you something about cardiovascular risk even though itself it isn't directly impacting on risk so in answer to your question I think one of the big issues with HDL cholesterol is that it's in inverse barometer of triglyceride efficiency of
• 59:00 - 59:30 triglyceride metabolism and again we talked about efficiency earlier you can only learn so much from measuring a fasting triglyceride after a 12 hour overnight fast it's useful it's the way we do it in terms of lipid panels but a lot happens after a fatty meal and a lot of that action is basically over in most people by 12 hours some people are extraordinarily effective at clearing their dietary fat and even their liver dry fat like mice others are not so
• 59:30 - 60:00 effective but they're fasting triglycerides may not necessarily even reflect that the HDL cholesterol does reflect that there's a complex as we discussed earlier complex frequent interaction and exchange between triglyceride rich lipoproteins and HDL with the net effect being the higher the triglycerides at any given time the lower the HDL is as a result of the complex interactions so if you can picture we do a lot of these experiments where we bring in people and we give
• 60:00 - 60:30 them a high fat milkshake we draw blood multiple time points after that milkshake and we measure triglycerides and all sorts of other things people differ a lot in their response to that high fat milkshake challenge the higher that triglyceride goes the area under the curve the lower the hdls are that relationship is extraordinarily strong so just like hba1c that HDL cholesterol is sort of reading out the 24-hour triglyceride metabolism much better than the overnight fasting triglyceride
• 60:30 - 61:00 measurement is sort of why hba1c is better than fasting glucose you know that's the analogy first of all I've never heard that before and that might be if I learn nothing else on this podcast and that is hands down the most amazing thing I have learned not just today but I'm going to go out and eliminate this week potentially this month that is super fascinating first of all people on this podcast have probably heard me gripe over the lack of integral functions in biology you know my background of course in math and
• 61:00 - 61:30 Engineering we love integrals right as imperfect as the A1C is as you said it is an integrator and it's so hard to find integrators you know ferritin sort of does it a little bit for iron but not nearly as well and you know the Holy Grail of course would be to find an integral of something like mtor activity or something like that but I've never before been presented with or confronted with this so I want to make sure we all understand this a little bit better so there's a couple things that you've said
• 61:30 - 62:00 there one is if you stick an IV in a person's arm let's just do that to go easy on them right so we're going to just be able to draw blood continuously or call it every 5 five minutes without poking them you bring them into a lab fasted you measure their HDL cholesterol you measure their trig so let's just say they show up in the morning fasted their trigs are 100 milligrams per deciliter HDL is 50 milligrams per deciliter so most people would look at that and say oh that's great person looks super healthy you give them a high fat shake and 30 minutes in you just start measuring every couple of minutes the
• 62:00 - 62:30 concentration of those two things I think most people somewhat familiar with metabolism would not be surprised to learn that the triglycerides will go through the roof as an aside anybody who has accidentally done a blood draw with their doctor after eating a meal when it was supposed to be fasting we'll be familiar with this right we see this from time to time when patients make mistakes you know they have a big fat breakfast before the blood draw and you get their trigs back in their four or 500 milligrams per deciliter but highly variable from person to person just to
• 62:30 - 63:00 be clear and highly meal dependent as well exactly very much depends on what the meal is so in this experiment though you're specifically giving them some something to elicit the biggest triglyceride response in the example I gave Dan let's say triglycerides go 100 125 150 all the way up to 400 before they start to come down that generates an area you could integrate that on the curve can you give realistic ideas or values for what the HDL cholesterol would do during that period of time the h0 cholesterol definitely dips during
• 63:00 - 63:30 that time in a way that's proportional to roughly proportional to the triglyceride levels but not anywhere near the same degree of magnitude right simply because it's starting lower and you have a constraint bottom versus no constraint time starting lower but also the Dynamics of its turnover are very different I think the key Point here is HDL is not just an integrator sort of acutely over that meal but chronically in your example the HL cholesterol might
• 63:30 - 64:00 go from 40 to 38 or 37 which doesn't sound like a lot after that one meal but the repeated meals that the individual is eating that are high fat and that repeated triglyceride Excursion has a more chronic effect a little like glucose in hba1c that keeps taking the HDL down over time until you get to kind of a new steady state so the acute effect on the HDL is real it's modest The Chronic effect on the HDL of that abnormal postprandial triglyceride
• 64:00 - 64:30 metabolism is quite substantial and that's why HDL is a good as you say integrator of this effect and actually what you just said Dan is kind of what I was hoping to go to next which is if everything I said were true that might not be enough to explain the full integral function because it probably captures some of what's happening outside of the meal just as hemoglobin A1c doesn't only reflect what would be captured in an oral glucose tolerance
• 64:30 - 65:00 test it captures what's happening over 90 straight days when you're eating when you're not eating exactly and that's also why there's a very strong statistical relationship between fasting triglycerides and low and the HDL so the fasting triglycerides themselves are still affecting HCL metabolism it's just that the postprandial part is also a key component so let's then again just one more time sort of reiterate the lagging nature of HDL cholesterol through HDL biology to
• 65:00 - 65:30 what's happening with the efficiency of maybe for lack of a better word lipid partitioning the lagging nature meaning the integrating over time yeah exactly let's use an example so you've got a person who is exercising and so you have two people who are similar except that you know one is very insulin resistant and one is quite insulin sensitive the insulin resistant person is going to have a higher level of insulin all
• 65:30 - 66:00 things equal they're going to have a more difficult time oxidizing free fatty acid so as energy demand goes up from the muscle they're going to be more likely to utilize glycogen as opposed to utilizing triglyceride so at any point in time you might measure differences in glucose differences in lactate you might well you would see lactate as well but differences in triglyceride level you might also notice more fat in the liver or some fat in the liver of the insulin resistant person none in the insulin sensitive person into that situation even when they're
• 66:00 - 66:30 not eating they're quite different physiologically what is the HDL Discerning or doing in those two scenarios that's being reflected in the ongoing integral function of it the simplest most direct model is that the HDL is reflecting the 24-hour excursions and triglycerides like we were just talking about I think what you may be getting at is there are almost certainly other components of metabolism that the HDL is integrating and reflecting particularly
• 66:30 - 67:00 in the complex insulin resistance world we know insulin resistance has a lot of effects other than affecting triglycerides and insulin resistance I'm sure has effects that are affecting and are reflected by lowering of HDL what I can't tell you is exactly what those are that's an area that is still a topic of Investigation I will give you one hypothesis though and one that maybe I think has some Merit as you know
• 67:00 - 67:30 adiponectin is an adipocine secreted by fat that has an inverse relationship to insulin resistance so you know basically people who are insulin resistant of lower levels and people who are you know more insulin sensitive and adiponectin itself appears to have some direct effect on HDL metabolism in the right direction we could talk about it possibly by tweaking the liver and ways that then the liver affects HDL so where I'm really going with this although I have to say the data still are not
• 67:30 - 68:00 completely solid is that another way that insulin resistance is impacting on HDL is through a dipinectin secretion affecting HDL metabolism in a way that's completely different than the triglyceride hypothesis that I just put forth you follow me yeah and it's funny we used to measure out of connecting and leptin levels again one of those things I sort of stopped measuring do you think that that's a helpful biomarker independently and should that be something that's back on our plate absolutely fascinating to try to put
• 68:00 - 68:30 together these metabolic pathways in terms of its utility as a clinical marker I guess I'd have to be a little bit skeptical I'm not quite sure how I would use it in terms of guiding clinical care I mean I think that was sort of where we ended up which was look we get more actionable insight out of other metrics okay that was really interesting and again before we leave the pharmaco side of this can we talk for a moment about niacin oh sure it's been a while since niacin came up on a
• 68:30 - 69:00 podcast but this is an interesting drug because it clearly raises HDL cholesterol and it lowers APO B doesn't it it does it lowers triglycerides it lowers ape will be it lowers LDL all modestly but really Peter and niacin I just chuckled because niacin is one of these areas where we as lipidologists and me personally have to really eat a bit of crow there was a time when I prescribed niacin to a lot of patients with primarily the idea that it was the only thing we had to raise HDL this was
• 69:00 - 69:30 in an era where HDL is the good cholesterol and raising it must be good right I also told myself well niacin does lower triglycerides it lowers APO B it lowers LDL it also as I'm sure you know modestly lowers LP little a as well about 15 lowering of it yeah 15 20 yeah basically was was like this is a nice broad spectrum lipid lowering drug that you know not in place of but on top of a Statin for certain people who had certain lipid profiles mostly high triglycerides low HDL has to be
• 69:30 - 70:00 providing some benefit even in the absence of as you pointed out the clinical trials that really are a Cornerstone of cardiovascular medicine well the clinical trials you know got done the high trial which was a very well done trial which frankly just didn't show much benefit of niacin a blow to us but the field comes up with reasons why that trial may not have been right bottom line is one more trial run by Merck with a drug that also helped to potentially address some of the issues with niacin was done a very large trial
• 70:00 - 70:30 very well-powered trial and that also had really minimal or very disappointing effects on reducing cardiovascular events essentially those two trials killed niacin so over the next you know years patients would come back I would have the discussions that maybe you've had discussions with patients do like this you know that niacin I put you on you know eight years ago that you've been taking religiously despite the question that it causes when you take it I really think I have to tell you that
• 70:30 - 71:00 I'm not sure you need to take it anymore and it was a humbling experience to basically have a drug that I had prescribed quite a lot basically to tell patients that I don't think that in retrospect this is helping you much I do have a subset of patients who are so wedded to their niacin that despite that they haven't wanted to stop but the vast majority of my patients have stopped their knives and what's the mechanism by which niacin raised HDL cholesterol I think one is certainly triglyceride lowering like we were talking about
• 71:00 - 71:30 earlier but probably not just that because the increases in HDO were somewhat disproportionate to what you'd predict from the triglyceride lowering although again with the complexity it's a little hard to make that calculation so there probably is some other mechanism and to this day I don't think we really understand it we tried for a while to try to figure that out niacin is a very complex drug of course we're talking about niacin here in pharmacologic dosing not in the kind of vitamin dosing
• 71:30 - 72:00 we don't really know I think it's fair to say how nice and raises HDL Beyond its triglyceride lowering effect you know it's not a drug we used much if at all but the few times we did I was actually really amazed at how much it raised HDL cholesterol I mean it wasn't uncommon to go from 50 milligrams per deciliter to 90 milligrams per deciliter on a strong dose let's shift gears for a second and talk about something that we briefly touched on but I think we now want to go into a little bit more detail
• 72:00 - 72:30 if everything we've talked about so far is like somewhat complicated I actually think for me at least this next part especially the RCT stuff gets complicated so let's talk about what HDL lipidation delibidation and reverse cholesterol transport are because this is really where we start to get into some of the sophistication of the HDL and even the interaction with other cells like macrophages and things like that I'll start and then you can kind of lead me along because this can get quite
• 72:30 - 73:00 complicated but and maybe just to orient you Dan why don't we start with unless you have a better way to do it I'm totally open but if you're looking for a goal post to start in you want to start with a foam cell stuck in an artery wall or is there a different place you'd want to start the discussion that's a good idea so many of your listeners know that core Concept in atherosclerotic vascular disease is the macrophage that's taken up lipids and is now a so-called foam cell meaning it looks foamy under a
• 73:00 - 73:30 microscope because it has all this lit lipid and when you stain tissues the lipids become like bubbles within the cells and they become look Foamy the foam cell the lipid loaded macrophage is a core pathologic feature of atherosclerotic vascular disease it's also the first thing you see so careful studies that have really looked at vascular tissues in children and teenagers and young adults on the way up you basically see lipid-loaded macrophages accumulating in the
• 73:30 - 74:00 sub-intominal space in the intimal space in the large vessels before you start seeing some of the more complex features of infiltration of other leukocytes and extracellular Matrix and all the stuff that ultimately comes the complex atherosclerotic plaque there's been a strong belief for a long time that this is one of the core initiators of the process and I think that's probably true an analogy would be like with Alzheimer's the a beta being kind of the core initiator of the process leading to much more complex pathology so macrophages have very well as
• 74:00 - 74:30 established mechanisms for ridding themselves of cholesterol you know keep in mind no cell except the liver cell has the ability to metabolize cholesterol to other sterile species only the liver can do that cells can make plenty of cholesterol but the only way cells can deal with their cholesterol is to quote efflux the cholesterol to push the cholesterol out of the cell and get rid of it so if you think at the whole body level all of the
• 74:30 - 75:00 body is making cholesterol but that cholesterol ultimately has to come out of those cells into something this is where HDL comes in and ultimately get back to the liver where the liver then can metabolize it or directly excrete it into the bile then it goes out the intestine and the feces so all cells have to be able to do this and all cells in fact have the ability to push cholesterol out of their cells but macrophages really have to do it that is because macrophages are like kind of the dump truck of the body they're picking
• 75:00 - 75:30 up not only LDS cells and lipoproteins with cholesterol they're Scavenging cells dead scales apopsotic cells and of course all those cells have lots of cholesterol so macrophages need very very effective ways to rid themselves of cholesterol and they do have effective ways of doing that when those Pathways get overcome or less efficient the macrophage then builds up cholesterol and becomes the kind of foam cell that we're talking about macrovages have Transporters they have a very abundant
• 75:30 - 76:00 amount of this abca1 that we talked about earlier earlier we talked about it in the gut in the liver now I'm saying that macrophages have ABC A1 abca1 is one of the not the only way that macrophages rid themselves of cholesterol if you recall the main acceptor of cholesterol via abca1 transporting out of a cell is apoa1 this led now quite a long time ago to the general Paradigm that macrophage foam cells are building up cholesterol
• 76:00 - 76:30 because they're not getting rid of it effectively and that one of the best ways to get rid of it would be to promote these efflux Pathways via abca1 and other transporters that are being driven by apoa1 to HDL which then by my garbage truck analogy the garbage truck the I.E the HDL is picking it up in the periphery like the blood vessel and returning it to the liver dumping it off in the liver and then going back and doing its job again this process of quote efflux cholesterol
• 76:30 - 77:00 efflux from macrophages and frankly other cells particularly in the blood vessel wall has been for a long time now thought of as a key process that would help to protect against the early initiation and progression of the atherosclerotic plaque Peter that was long but that's the start well and I think that's look let's just make sure everybody understands what we're talking about here which is when we really talk about the positive valence of HDL
• 77:00 - 77:30 as a particle it's because of this right in large part this is a big piece of the positive Association presumably or negative association depending on the direction of hdlc we might see as we've been talking about it it really now speaks to function part of the problem it would appear is that very crude metrics like the amount of cholesterol in an HDL or even the number of HDL particles or the size of an HCL particle
• 77:30 - 78:00 those are basically the only things we can measure clinically at least those are so crude and so far removed from providing any quantification of the process you just described that I suspect in part that's why we are stuck in a way that we are not on the APO b side of The Ledger because so much of the damage caused by apob is simply captured in the number of them given the stochastic nature with which they enter
• 78:00 - 78:30 artery walls and get retained would you agree with that assessment I would absolutely agree with that so this process of cholesterol Leaf Lux as the sort of ideas evolved is if you will the first step in this broader physiologic process that Peter briefly referred to that we call reverse cholesterol transport or RCT different than a randomized control trial if forward cholesterol transport is basically the cholesterol coming out of the liver into vldl and LDL and then depositing in tissues like the artery the reverse transport is the picking up
• 78:30 - 79:00 of the cholesterol putitively via API 1 and HDL and returning it back to the liver this process of reverse cholesterol transport plausibly and I think some data at least in animal models is related to protection against atherosclerosis that is the more effective you are at the integrated process of not only picking up the cholesterol via efflux but effectively returning the cholesterol to the liver for excretion the more you would protect against
• 79:00 - 79:30 atherosclerosis as the theory goes and I'll just remind you about our example with srb1 that's the terminal sort of one of the terminal steps where the HDL is dumping off the cholesterol if you interrupt that process your HDL goes up but the process of reverse cholesterol transport is being constipated and therefore there's increased risk of atherosclerotic cardiovascular disease one of the great goals of the field has been can we promote that first step of
• 79:30 - 80:00 the process can we figure out a way to promote the driving of the efflux process from the Mac of Ages and maybe other cells in the atherosclerotic plaque to acceptors like HDL in order to protect or maybe even regress atherosclerotic plaque shrink it as a way of trying to reduce risk and I'll just say that as we move into this next phase of complexity I think what's pretty clear is it's not the mature HDL particle you know when we measure HDL
• 80:00 - 80:30 cholesterol that's what we're measuring is the cholesterol in the mature particle that's almost certainly not the particle that is driving this first step of the efflux of the cholesterol from the foam cell and the macrophage and and that's maybe why simplistically raising HDL cholesterol like with C to be inhibition and doesn't actually reduce the atherosclerto cardiovascular disease events but are there other ways more creatively that we might be able to
• 80:30 - 81:00 drive that process and also to Peter's earlier functional point might it be that different people even with identical HDL cholesterol levels have different function of their HDL one person with an HDL cholesterol of 50 might have something about their HDL pathway that is like super functional at driving eflux whereas another person with the same HDL cholesterol doesn't do nearly as well and if we could measure function efficiently might we have a better way
• 81:00 - 81:30 of assessing risk and maybe even targeting interesting therapies more so than just measuring this fairly not so Dynamic measure of HDL cholesterol itself there's more to say there Peter but I'll turn it back over to you well no I mean I think you illustrate the very important distinction between static biomarkers and dynamic biomarkers and we have very few Dynamic biomarkers you know an ogtt and all glucose tolerance dynamic biomarker in a sense but most things are very static and static things allow us to miss flux so
• 81:30 - 82:00 that example you gave of two people whose HDL cholesterol is both 50 milligrams per deciliter we have no clue what the velocity through the HDL is in one of those cases it could be a bump on a log and the htl is not really doing a heck of a lot and in the other that could be the busiest Beaver on the face of the Earth just transporting lipid out of foam cells right back to the liver back and forth back and forth back and forth and that could be the most industrious little guy on the Block and you could be
• 82:00 - 82:30 in a totally different risk situation as a result of that so going back to the RCT how often is it happening that in APO bite-bearing lipoprotein let's just call it an LDL is floating around so not yet an artery wall but on his way there presumably and an HDL come along and they Collide in the artery itself and delipidation takes place so the HDL says hey I'm going to take some of your cholesterol away and take it back to the liver now which by the way ldls do as
• 82:30 - 83:00 well I mean ldls are obviously carrying cholesterol but not as a reverse cholesterol transport process but yeah the scenario I describe does that occur often no I don't think so in fact as we discussed earlier with CTP the directional flux of cholesterol in the blood blood is more from HDL to ape will be containing lipoproteins rather than the other way around so I'm pretty comfortable in saying I don't think that what you just outlined is a way that HDL AGL doesn't directly delipidate LDL no
• 83:00 - 83:30 no I think it's more about if it's happening at all I want to say all this is couched in this is the Paradigm that we're dealing with but where there's still a lot of uncertainty about it but if it's happening at all it's really more that something about HDL or something apoa1 is more interacting with cells to promote efflux of cholesterol rather than with other lipoproteins like apob container hyper proteins what do you think the future could look like here in terms of commercial assays to measure HCL function I know that we're a long way away from that so maybe I
• 83:30 - 84:00 should start with something even more basic which is what would it take in the lab to measure HDL functionality if resources were unconstrained no that's where I wanted to go so first I want to say that you know several years ago with this concept of reverse cholesterol transport as a dynamic process we developed an assay in mice that simply speaking involved taking cholesterol-loaded macrophages with labeled cholesterol injecting them into the mice and then following that
• 84:00 - 84:30 label all the way through the HDL to the liver to the gut to the feces and we called that integrated reverse cholesterol transport and we showed in a variety of different genetic and pharmacologic approaches that when you tweak that process either up or down it mirrored the effect of that process on atherosclerosis what I'm really trying to say is something that promoted that process and made it more efficient also reduced atherosclerosis something that constipated that process increased atherosclerosis it gave us a lot of
• 84:30 - 85:00 confidence frankly it gave the feel a lot of confidence that integrated measure of reverse cholesterol transport is actually relevant to atherosclerto cardiovascular disease at least in mice so that brings me to humans we can't do the type of experiment I just described in humans it's not feasible as a research or as a clinical assay so we thought long and hard about how can we start to think about doing this in people and developed what I'll call an anex Vivo cholesterol reflux assay where
• 85:00 - 85:30 the concept is we took someone's blood or plasma we isolated the HDL specifically we got rid of the apob contained lipoproteins and then put that on cells that were labeled with cholesterol and we measured the effectiveness by which that HDL removed cholesterol from cells what kind of cells what we found as I think you know is we were really struck with how different individuals hdls were at their ability to extract cholesterol from cells even with the same HDL cholesterol
• 85:30 - 86:00 level and it's sort of affirmed this concept that HDL cholesterol is not really telling us or informing us on the efficiency of the function of HDL at least in this case the function define mind as the ability to extract cholesterol from cells and so we went on to use that in larger numbers of individuals and showed that actually that was much more predictive of risk of coronary heart disease than just measuring HDL cholesterol even when you controlled for HDL cholesterol statistically and many
• 86:00 - 86:30 others have shown the same thing so I think it's pretty well established at this point that this so-called cholesterol reflex capacity measurement of HDL is a better marker or predictor of risk than just measuring HDL cholesterol consistent with the idea that function is important and that perhaps if we could increase function we could maybe have a mechanism for reducing risk now Peter you asked about the clinical Aptoide of that asset you know I get asked all the time by
• 86:30 - 87:00 patients and referring doctors can you measure my patient's HDL function there's a lot of effort in this regard full disclosure I was part of starting a little company now several years ago called Vassar strategies investor strategies does do this measurement in a very reproducible sort of way mostly related to biomedical biopharma research but there is a lot of interest in trying to bring this clinically and there are other assays that are being developed you know when you're using radioactivity it's a little you know it's cumbersome
• 87:00 - 87:30 for a clay throughput clinical assay and others are developing assays that are cleaner and simpler and faster and cheaper I think there's a chance we could have a more widely available clinical assay to us for this purpose within the next say two to three years right now it's still under development two follow-up questions there Dan one is just a technical question on the assay what type of cell are you using to measure the e-flux capacity well when we first sort of pioneered
• 87:30 - 88:00 this work we used a mouse macrophage cell line called the j774 cell we have done it with human macrophages as well and so have others we like to think that the Mac of age is the most relevant cell type for reasons we discussed yeah that's the answer and then I guess the second question is using the hypothetical but probably somewhat real example of we'll take a hundred people that have an HDL cholesterol that's about the same we do this assay and we rank order them in
• 88:00 - 88:30 Effectiveness you're saying that that rank order of Effectiveness correlates directly to risk are you saying directly related to risk by proxy I.E other measurements like insulin resistance apob or you saying actual outcomes the first study we did and published was cross-sectional with clinical coroner disease so basically calcium scores or things like association cross-sectionally with prevalent disease then we basically said we need to know if this is predictive of incident
• 88:30 - 89:00 disease events that occur so we went to colleagues who did the Eric Norfolk study which you're probably familiar with a very large prospective study in the UK in Europe they provided samples and we measured this in a very large number many thousands of samples in a baseline in people who had been followed for 10 plus years and we showed even in that setting that the eflux capacity was predictive of incident cardiovascular events so yes these are hard events not just proxies like measurement of corn or
• 89:00 - 89:30 calcium for example which is again fascinating how well does that prediction hold up if you corrected for other things that could be measured in the blood such as insulin resistance triglyceride or apob we did do the statistical analyzes correcting for clinical risk factors including of course HL cholesterol itself we corrected for things like BMI and presence of diabetes dichotomous presence of diabetes if memory serves we
• 89:30 - 90:00 didn't attempt to correct for like a sophisticated marker of insulin resistance like home or anything because I'm not sure we even had that data so your point is well take at some point is this causal or is it still associative but just even better associative because it correlates with things even better than HDL cholesterol and I think that's why we need of course Interventional studies that actually test the hypothesis well or even could we use it there could be a hybrid there right which is it's absolutely causal but because it's so
• 90:00 - 90:30 difficult and complex to initiate at scale what if we use AI to figure out that it's equivalent to a new metric that is a composite metric of things that we can measure as biomarkers if that makes sense I hear what you're saying and that would be a great thing to think about in our paper in Epic Norfolk we did correlations of the flux capacity with lots of different things I frankly have to go back and look at that and remind myself if we had like fasting insulin or
• 90:30 - 91:00 anything because I think that starts to get more at the insulin resistance component but um you're absolutely right we may be able to find markers that in composite would predict e-flux capacity rather than having to measure the e-flux capacity itself I'm not convinced we'll be able to do that but I think that it's a good thought because the analogy that comes to mind is you know certain Labs use a series of NMR metrics to predict insulin resistance which I've always found not
• 91:00 - 91:30 that interesting frankly because we can measure insulin resistance so easily that using NMR to add another insulin resistance metric it seems a bit backwards but the idea was they were able to basically look at the NMR Spectra of all the lipoproteins and impute a composite metric that came back so if you could do that in the other direction which would actually be the valuable Direction it could be amazing in other words if there was an HDL function score built out of X Y and Z anything else before we leave
• 91:30 - 92:00 the topic of kind of measurement we haven't really talked about the NMR side of the equation that's probably a bias because we don't use NMR but clearly there are Labs out there that will count the number of HDL particles and spit out in hdlp anything you want to say about hdlp or anything like that yeah the overall number of particles is obviously correlated with HDL cholesterol but is a different measure because HCL cholesterol is just that amount of cholesterol carried in the HDL whereas
• 92:00 - 92:30 the particles are more analogous to sort of measuring APO B the meaning total particle number you know I think the data on balance suggests that HL particle number is a little bit better than HDL cholesterol at predicting risk we haven't like formally compared HDL particle to cholesterol reflex capacity the functional measurement fundamentally it's another static measure though and so while has maybe some limited predictive value I don't think it takes us that much further in terms of trying
• 92:30 - 93:00 to get at where we're really trying to go is better predictions of risk particularly in a setting where we might want to intervene to actually try to reduce risk let's talk about something you mentioned kind of in passing a couple of times Peter before we leave this topic though I do think it's important to remind your listeners that this concept of promoting the efflux and reverse cholesterol transport pathway is being tested with another intervention called CSL 112
• 93:00 - 93:30 it's a form of apoa1 that's been complexed with lipids in a so-called recombinant HDL particle is being tested for impact on cardiovascular outcomes in the setting of acute coronary syndromes so people have come in been randomized to four weekly injections of this apoa1 containing recombinant particle which is very effective at promoting cholesterol leaflux based on all the work that's been done with the idea being that this may directly impact the plaque and
• 93:30 - 94:00 impact on cardiovascular events so this is I would say the closest thing we have to a formal test of the cholesterol efflux hypothesis as an intervention in terms of whether it will reduce risk those of us in the field are on the edges of our seats you know it'll be a little while to really see what this trial shows I do think it's going to be interesting either way so earlier Dan you mentioned kind of briefly the
• 94:00 - 94:30 association of plasma apoa1 and HCL cholesterol with neurodegenerative diseases such as Dementia or Alzheimer's disease I don't know if it extends to Parkinson's or Lewy Body what do we know about that well this is a I think a fascinating new area of HL biology that has a number of components in that that's still being investigated I want to maybe start by bringing in apoe we haven't talked about Apu e a buoy clearly has a role in apob containing lipoprotein metabolism and mediating the uptake of
• 94:30 - 95:00 those Remnant particles into the liver can you actually explain this a bit more because most people hearing this are going to think of apoe the Gene and of course the gene for apoe people are going to be familiar with it exists in three isoforms two three and four but of course these things combine so you have six combinations of an apoe genotype and of course the gene codes for a protein so I mean I assume everybody has the same apoe protein you're going to have different amounts of it and different
• 95:00 - 95:30 potentially functionality depending on the combination of which Gene produced it exactly apoe is possibly one of the most fascinating genes and proteins in human biology in terms of its roles and its and the isoform issue and its relationship to disease so as you point out there are three common isoforms of apoe apoe3b being the so-called wild type are the most common you know in lipidology we focused a lot on Apu E2 because if you inherited two copies of
• 95:30 - 96:00 APO E2 that form of apoe is defective in binding to the LDL receptor and the other receptors that mediate uptake of Remnant lipoproteins both chylomicron remnants and bldl Remnants and therefore if you homozygous for apoe2 you're at risk for so-called again the terminology is bad type 3 hyperlipidemia which is basically a Remnant clearance disorder these individuals can't clear their remnants appropriately they get high triglycerides and cholesterol they
• 96:00 - 96:30 also are at increased risk of atherosclerto cardiovascular disease it's a classic lipidology thing and these patients require phenofibrates to bring down the vldl and triglyceride they respond to the to a lot of the standard LDL lowering therapies like Statin and acetamine they even respond to pcsk9 inhibition but sometimes we have to add on fibrates as well to maximally control them depends on how severe they are and yet those people and by the way that's the only genotype I've never seen it's much more rare than the
• 96:30 - 97:00 4-4 homozygotes but the tutu would come with about a 20 risk reduction relative risk reduction in Alzheimer's disease but paradoxically comes at this higher risk of ascvd exactly so it comes at higher risk of lipid disorder and ascvd but that's exactly why I brought up apoe in response to your comment about neurodegenerative disease so as probably a lot of people know who are listening the APO E4 as you just pointed out the apoe4 form which is present about 25 of
• 97:00 - 97:30 people so it's quite common and even in the homozygous form you know certainly plenty of people out there who have both two copies is in a dose-dependent way the major genetic risk factor for Alzheimer's disease no question about it and as you said Peter April E2 which is bad for your lipids in the blood is actually protective against Alzheimer's it's absolutely fascinating biologically there has been so much work to try to understand how apoe is interfacing with
• 97:30 - 98:00 Alzheimer's disease so apoe is made in the brain it's made by cell types like microglia in the brain and it's a lipid binding protein that you know transports lipids and now we know from genetics of Alzheimer's that there are lots of other lipid genes that are related to Alzheimer's so the story starts with the fact that apoe made in the brain is somehow impacting on Alzheimer's risk and if you have this form of apoe4 and especially if you have two forms of apoe4 you were at very substantially
• 98:00 - 98:30 increased risk of Alzheimer's for reasons that we still don't fully understand but as a lipidologist I think it has something to do with lipid transport in the brain so that brings me to HDL the apoe and the CSF and in the brain is mostly made there the newer developments that are relevant to apoy 1 and HCL are that there is clearly APO A1 in the brain and in the CSF 8.1 is not made in the brain so apoa1
• 98:30 - 99:00 gets there somehow through the blood which I'll come back to but there's now quite a lot of observational data that strongly suggests that apoa1 is protective against neurodegenerative disease now this is associative data it doesn't prove causality but the reason I think it's plausible is that two of the major genetic risk factors for Alzheimer's that are expressed in the brain are ABC
• 99:00 - 99:30 A1 remember that lipid transporter that rid cells of cholesterol and that apoa1 interacts with and promotes and ABC A7 a very close relative of abca1 that structurally looks very similar and that we don't know exactly what it does but I think it's a safe bet that it's transporting some sort of lipid to Something in the extracellular space whether that's eight way one or apoe or something else so the plausibility of
• 99:30 - 100:00 April A1 being protective against neurodegenerative disease particularly Alzheimer's is quite high and frankly there's a lot of work to be done to try to figure it out there's one other point I'll make which is the blood levels of apoa1 and the CSF levels of 8.1 and the relatively small number of studies that have measured both in the same people are not that well correlated so it's not simply a matter of if you have a high level of 8 way 1 in the
• 100:00 - 100:30 blood that's going to generate a high level of API 1 in the CSF so what that probably means is the processes that are happening that get the API one across the blood-brain barrier are highly regulated processes that a little like the cluster leaflux Story Probably differ from person to person and aren't directly being driven by the level of 8-way one in the blood where I'm really going with this is this concept that if we can figure out how that happened if we could somehow promote more apeway1
• 100:30 - 101:00 going into the brain into the CSF the data suggests that that might be a very interesting opportunity to blunt or reduce risk of Alzheimer's I find it fascinating as you can tell Dan do we know if this relationship is stronger or weaker as a function of apoe genotype is the effect more pronounced do we have enough data to parse out that type of a relationship so I'll give you an example yeah that's a really super question and
• 101:00 - 101:30 I don't think we have big enough data sets yet to be able to parse it out in terms of by apoe genotype to figure that out but I have to go back and look for that but I don't think we know that yet do you have any idea why Labs have not developed what would be very easy to do which is just a commercial assay for apoe concentration there's certainly some data to suggest that apoe concentration might be more relevant than apoe genotype although of course it's highly influenced by apoe genotype but you
• 101:30 - 102:00 could almost think of it as a gene expression measurement accrued measurement of gene expression for apoe is that something that you've seen or used even in the lab you're talking about apoe in the blood yes not in the system correct just to be clear there are automated assays for a buoy we run one routinely in our lab I think it's not a clinically used assay no I've never even seen a CLIA based assay for it right I think mostly because it isn't that helpful in The Limited studies that
• 102:00 - 102:30 have been done which admittedly maybe aren't as voluminous as they should be it isn't that really helpful in terms of predicting cardiovascular risk total plasma apoe oh I was thinking more for neurodegenerative disease has that been looking oh well you know I didn't say it but the levels of aprily in the CSF and the levels of apoe in the blood for the few studies that have measured both in the same people also do not correlate much at all you would need CSF apoe if you wanted to do anything with this exactly that's what I'm getting at you would need to be able to do it I would
• 102:30 - 103:00 not be surprised if someone develops an assay for apoe concentration in the CSF as a clinical tool because there I think that might be highly relevant interesting so here we have basically HDL potentially being protective in the brain and presumably doing so via APO A1 potentially offsetting some of the apoe problem apoe being as I think one of our previous guests referred to as as kind
• 103:00 - 103:30 of the general contractor of cholesterol in the brain yeah does HDL do anything with nitric oxide I think I remember reading something about promoting sort of endothelial NOS activity nitric oxide synthase activities that a major issue there's been a variety of other quote functions that HDL has been reported to do which I think are absolutely real their relevance to human disease and pathophysiology I think are less clear but one example is what you just said so couple investigators most notably Phil
• 103:30 - 104:00 Charlotte and Dallas has shown very clearly and beautifully in cells and mice that HDL can promote nitric oxide production in a way that would be expected to be beneficial both in terms of blood pressure lowering and it may be protection against atherosclerosis and that sob1 the receptor we've been talking about is also present on endothelial cells and mediates at least part of that effect of HDL it's a fascinating observation that is absolutely I think solid Translating
• 104:00 - 104:30 that observation to relevance in humans I think is challenging but I think plausible you know another we've been talking about insulin resistance I'm sure you're aware of the data that suggests that HDL can interact directly with skeletal muscle in a way that promotes insulin sensitivity no I'm not fascinating work again I put it in the same category of solid in terms of what it's been able to show mechanistically a little bit unclear and relevance to
• 104:30 - 105:00 human disease and Physiology I think a still a little bit unclear these are just two of of the other types of things that HDL has been shown to do that would be putatively beneficial but are of Uncertain relevance to real human disease you know it's even more sort of removed than that because even if we knew mechanistically that this were sound we're still back in the same area we are with ascvd in ascbd there's really very little ambiguity about the utility of HDL The Beneficial utility of
• 105:00 - 105:30 HDL and yet we're standing here with our hands in front of us saying well what can we do about it clinically as a physician as a patient what do I get to do about this knowledge that hdls are helpful particles when I can't measure the manner in which they do their job and the only things that I can measure are as useless to me as my eye color basically and then we're expanding into and look what they can do in muscles and
• 105:30 - 106:00 look what they can do in insulin sensitivity and look what they can potentially do in the brain it really comes back full circle to how we open the discussion Dan which is this is such a complicated area of biology that I would guess it has to be considered the next Frontier of the lipid space I mean when we take a step back and put ascvd in the context of cancer and neurodegenerative diseases right so these are the big three killers in the modern world we know so much more about asebd and we have so many more
• 106:00 - 106:30 tools to effectively treat it we know a bit about these other diseases but in case of Alzheimer's is we don't have a single tool to do anything about it in the case of cancer most of our tools do nothing 90 of the tools do nothing I.E they barely extend median survival but don't cure people but in ascbd we can really move the needle and yet you could argue half of the field we still know nothing about and is there going to be a renaissance you think or are we up against some technical limitation on this inability
• 106:30 - 107:00 to measure function and I say that in a practical way I mean yes I think you're already measuring function in the lab but is this a bridge too far for the clinician well I'm going to separate that into using a measurement of function for risk prediction and then the implications for intervening therapeutically I think that HDL function say cholesterol reflux has the ability to allow us to more specifically assign risk better than just measuring HDL cholesterol I think
• 107:00 - 107:30 realistically we need a good reproducible easy to run automatable assay that then is tested in large numbers of people and shown to predict risk better than HCL cholesterol itself I feel like knowing what I know is going on in terms of developing those assays that there's a decent chance that we're going to get there but it's not just the development of the assay which actually there are several assays now that are but it's the proving that the
• 107:30 - 108:00 measurement actually enhances risk prediction enough not just incrementally but enough to make it actually worth doing in clinical practice I think there's a I'm not going to say 100 but I think there's a more than 50 percent chance that we're going to see at least some assay come out that will allow us to do that and then it will be you know frankly Physicians like yourself and like Tom Day Spring who pick up that assay and start using it in their patients and start trying to get a sense for whether it's useful in the context
• 108:00 - 108:30 of a sophisticated preventive clinical practice I think with regard to intervention the study I talked about is huge in terms of this let's just assume that that study is positive four four infusions weekly infusions significantly reduces cardiovascular events in patients with ACS after 90 days if that study is positive if you think about that the implications for that product but more importantly for the field that showing that actually
• 108:30 - 109:00 triggering cholesterol leaflux via infusion of that particle that type of particle that will rejuvenate the field of cholesterol efflux and reverse cholesterol transport as a therapeutic Target for intervention I think if that trial is not positive I think the concept of intervening around HDL and reverse cholesterol transport for purposes of ascvd is probably past recovery that would be my view and even that CTP inhibitor that I mentioned
• 109:00 - 109:30 that's still in development it's really more about reducing apob than it is about raising HDL when does that trial readout the function trial I should have refreshed my memory on that I just can't remember where is it being done how many centers roughly it's a global study there's centers in you know us and Australia and Europe it's a classic Global large cardiovascular outcome trial I think the leaders of the trial I think are in Boston remind me does it have a fancy acronym yet yes and I'm embarrassed to say that I'm not quite coming up with that either
• 109:30 - 110:00 you will figure that out and it'll be in the show notes if I could just follow up on your next Frontier comment I don't think HCL per se is the next Frontier but I do think lipid metabolism in the brain is one of the next Frontiers I really do with regard to neurogenic disease but also other brain function I say that as a long-term lipidologist who has focused primarily on the blood so I admit my biases and looking for things that we can apply as lipidologists our expertise to but I do think
• 110:00 - 110:30 understanding lipid metabolism in the brain and its relationship to disease you know the brain is of course the most lipid Rich organ of any organ in the body has been an under-investigated area that we have a lot to do but where I think we're going to be uncovering some very interesting things that with luck have implications for therapeutic intervention to prevent neurodegenerative disease Dan it's hard to go anywhere from here that is I mean both exciting and important in ways that
• 110:30 - 111:00 are rarely captured even in this subject matter so I want to thank you for taking a subject matter that is so complicated that I've largely shied away from really doing anything on it in the AMA series that we do and so eloquently describing it and really using if someone's listening to this and this is the first podcast they've ever listened to of ours they might think oh my God that podcast is too technical but I think for regular listeners they will appreciate that you really did a great job simplifying a very complicated subject matter and
• 111:00 - 111:30 certainly did a better job than I would have ever been able to do not simply because I don't know as much but because the ease with which you were able to speak about this is impressive so thank you for taking the time thank you for doing that and most importantly of course thank you for your work in this field we I think collectively look forward to seeing how things shake out over the next decade thanks very much Peter I really enjoyed it thank you for listening to this week's episode of the drive if you're interested in diving deeper into any topics we discuss we've created a membership program that allows us to bring you more in-depth exclusive
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