6 Things you need to know about your cholesterol panel
Dr. Ronald Krauss pioneered LDL particle science—and he says most people are missing the most important parts of their cardiovascular risk picture
Dr. Ronald Krauss has spent four decades studying the relationship between lipoproteins and heart disease at the Children's Hospital Oakland Research Institute. His work on LDL particle size—including the discovery that LDL comes in distinct subtypes with dramatically different levels of cardiovascular risk—has reshaped how scientists and clinicians think about cholesterol. In a recent appearance on A Whole New Level, he broke down six things he wants you to understand about what your cholesterol numbers actually mean.
1. Cholesterol doesn't travel alone—it travels in particles, and the particles are what matter
When most people think about cholesterol, they think about a single number. But cholesterol in the blood doesn't exist on its own; it's packaged inside lipoprotein particles—molecular structures that also carry proteins and other fats. It's these particles, not free cholesterol, that enter artery walls and drive plaque formation. "When it comes to mechanisms by which cholesterol impacts heart disease risk," Dr. Krauss explains, "we have to start talking about lipoproteins, not just cholesterol."
The most familiar of those particles is LDL, low-density lipoprotein. But LDL is not a single uniform thing. It's a family of particles that vary in size, density, and, critically, in how damaging they are to arteries. Understanding that LDL is heterogeneous—and that the standard LDL cholesterol number obscures that heterogeneity—is the first step toward a more accurate picture of cardiovascular risk.
2. The journey from VLDL to LDL explains why triglycerides and carbs are central to the story
The liver is where lipoprotein metabolism begins. It secretes large, triglyceride-rich particles called VLDL (very low-density lipoproteins) into the bloodstream. As enzymes break down the triglyceride in these particles, releasing fatty acids into muscle and fat tissue for energy or storage, the particles progressively shrink. They pass through an intermediate stage (IDL), and ultimately become LDL. Every LDL particle in your blood is the downstream product of a VLDL particle your liver made earlier.
This pathway explains why triglycerides matter so much. More dietary carbohydrates—especially processed grains and sugars—prompt the liver to synthesize more fatty acids, which get packaged into more triglyceride-rich VLDL. "The more carbohydrates one consumes," Dr. Krauss says, "the more of these triglyceride-rich lipoproteins are produced in the liver and ultimately secreted." The particles that result from this high-triglyceride starting point tend to shrink down into the smaller, denser LDL subtypes that are most strongly associated with cardiovascular risk.
3. Small, dense LDL particles are more dangerous than large ones—for several compounding reasons
Not all LDL particles are equally harmful. Small, dense LDL has a cluster of properties that make it particularly toxic to arteries compared with large, buoyant LDL. It binds more readily to artery walls, it promotes inflammation, and it's more prone to triggering the plaque rupture that causes heart attacks. But there's an additional mechanism that amplifies the damage: small LDL lingers in circulation longer.
The liver clears LDL from the bloodstream via LDL receptors, but small LDL interacts poorly with those receptors. "Small LDL particles are less susceptible to that uptake process because they interact less effectively with receptors in the liver," Dr. Krauss explains. The longer these particles circulate, the more time they have to encounter artery walls. "The residence time—the amount of time that such particles are present in the circulation—is a key determinant of heart disease risk." Exercise and maintaining a healthy weight both accelerate clearance, reducing exposure time.
4. Lp(a) is a silent risk multiplier that up to a third of the population carries—and most people have never been tested
Lipoprotein(a), or Lp(a), is a distinct particle built on an LDL scaffold, with an additional protein called apo(a) attached. It's produced through pathways almost entirely controlled by genetics, which means diet and exercise have little effect on it. And it operates through a "triple whammy" that makes it especially dangerous: it delivers cholesterol directly into artery walls, it promotes inflammation, and it promotes thrombosis—clot formation. "On a particle basis," Dr. Krauss notes, "it's actually as toxic or more toxic than these other lipoproteins."
Despite being present in roughly one-third of the population at elevated levels, Lp(a) has historically been ignored in clinical practice because there were no treatments to lower it. That is changing. Genetic therapies that can suppress Lp(a) production at the gene level are now in late-stage development. Even before those treatments arrive, knowing your Lp(a) level is actionable: high Lp(a) is a signal to be more aggressive about lowering LDL and other modifiable risk factors, and to screen family members who may have inherited the same genetic predisposition. "It's just a silent condition which you won't learn about unless you measure the test," Dr. Krauss says. He measures it in every high-risk patient he sees.
5. ApoB is a better starting point than LDL cholesterol—and particle testing goes further still
Standard LDL cholesterol measures the amount of cholesterol carried inside LDL particles, not the number of particles themselves. Two people can have the same LDL cholesterol reading and very different numbers of particles—because small, dense LDL carries less cholesterol per particle than large LDL. Apolipoprotein B (ApoB) captures something more fundamental: each lipoprotein particle associated with cardiovascular risk—VLDL, IDL, LDL, and Lp(a)—carries exactly one ApoB molecule. So ApoB is effectively a direct particle count across all the atherogenic lipoproteins at once.
For most people with borderline lipid levels—not dramatically elevated LDL, but maybe triglycerides trending up, some family history, or a general sense that the standard panel isn't telling the whole story—ApoB is the logical next step. Beyond that, specialized tests using nuclear magnetic resonance (NMR) or ion mobility can break down LDL into its subtypes by size and number. These tests aren't widely used, and standards for interpreting them are still evolving, but Dr. Krauss views them as the most precise tool available: knowing whether high ApoB is driven by small or large particles changes what interventions are most likely to help.
Heart Health playbook
Evidence-based levers for LDL, ApoB, and long-term cardiovascular risk—how to test, what to target, and how diet, sleep, and movement fit together.
6. Interventions should match the lipoprotein pattern—and carbohydrate reduction matters more than saturated fat for most people
The standard advice for high LDL has long been to cut saturated fat. Dr. Krauss's research suggests this is at best incomplete and at worst misdirected for many patients. Saturated fat primarily raises large LDL, which is the less dangerous subtype. The triglyceride-driven pathway that produces small, dense LDL is much more responsive to carbohydrate intake than to saturated fat. "Carbohydrates, and in particular processed grains and sugars, have a much more important effect on those types of particles than saturated fat."
This means the right dietary intervention depends on the lipoprotein pattern. For someone whose high ApoB is driven by elevated large LDL, moderating saturated fat may help. For someone whose profile shows elevated small LDL or high triglycerides—signs of metabolic stress—carbohydrate reduction and weight loss are the more targeted lever. Beyond diet, exercise improves clearance of remnant lipoproteins; weight loss, particularly reducing visceral fat, addresses the underlying insulin resistance that feeds the whole triglyceride-VLDL-small LDL cascade. Statins reduce LDL broadly but have modest effects on particle distribution, which is one reason medical management should ideally follow a more precise diagnostic picture.
The bottom line: your standard cholesterol panel is a starting point, not a complete answer
A basic lipid panel tells you the total cholesterol content of your LDL—useful information, but not sufficient on its own to assess cardiovascular risk accurately. Adding ApoB gives you particle burden. Adding Lp(a) tells you whether you carry a genetically elevated multiplier of risk most people don't know about. And in cases where the picture remains unclear, LDL particle subtype testing can reveal whether your risk is being driven by the metabolically dangerous small LDL fraction. "The borderline situations are where these measurements become most useful," Dr. Krauss says—and borderline is where most people actually are.
FULL TRANSCRIPT:
Why Your LDL Score Doesn't Tell the Whole Story | Dr. Ronald Krauss & Mike Haney
In a recent episode of A Whole New Level, Levels editorial director Mike Haney sits down with Dr. Ronald Krauss, senior scientist and director of atherosclerosis research at Children's Hospital Oakland Research Institute and one of the world's foremost experts on lipoproteins and cardiovascular disease. Krauss has spent more than four decades studying how different forms of cholesterol-carrying particles in the blood drive heart disease risk — including pioneering research on LDL particle size that has reshaped how clinicians think about the standard cholesterol panel.
The conversation covers why the familiar HDL/LDL story is far too simple, how triglycerides and carbohydrate intake connect to the most dangerous forms of LDL, what LP(a) is and why it may affect up to a third of the population, which tests beyond the standard panel are worth seeking out, and why metabolic syndrome — not just a high cholesterol number — may be the more important story for most people.
"Focusing exclusively on saturated fat is missing the point that it's really the food that contains the saturated fat that matters." — Dr. Ronald Krauss
Why cardiovascular disease is still the leading killer — and what we're missing
Mike Haney: Dr. Ronald Krauss, thank you so much for joining me today. Cholesterol is one of those topics where the more I learn, the more confused I get. I come at this from the perspective of trying to understand what's going on in the research and then translate that for the general public. And cholesterol is just one of those spaces where when I didn't know anything, I thought I knew exactly what was going on, and then the more I learned, the more confused I get. So I want to start just maybe high level, because you've been at this an awfully long time and done some really seminal work here. Why do you think cholesterol is still a very debated topic — or is it not as debated within your community?
Ronald Krauss: Within the community of researchers who are really looking at this, the debates such as they are are mostly happening online with people who don't really know what they're talking about. I don't think there's any disagreement among experts in the field or physicians in general that elevated blood levels of cholesterol present a risk for heart disease. I don't know that there's been serious controversy about that. I know there are some groups that have challenged the relationship of cholesterol to heart disease, but I think that really does not represent any scientific evidence.
So from the standpoint of that simple connection — high cholesterol, high risk of heart disease — I think we can start with that as being accepted. Now, some of the controversies come into play when one tries to put this in context of the overall risk of heart disease. How does this play into other factors that may influence heart disease risk? What particular forms of cholesterol in the blood are most strongly related to heart disease? That's where some of the controversy lies, and I'd be happy to dig into that with you. But I do want to start off by not challenging the very strong evidence that cholesterol levels are a factor that influences heart disease risk.
Mike Haney: We've known about this general story of cholesterol for quite a long time — that high cholesterol is a risk factor for heart disease. We've had tools like statins for decades. And yet cardiovascular disease remains the number one killer for men and women by quite a bit. Why do you think that is? Are we making progress?
Ronald Krauss: There has been a substantial reduction in risk of heart disease over the last several decades, and this has been attributed to a variety of factors, including some changes in dietary practices, the introduction of cholesterol-lowering drugs — in particular statins — and the use of procedures that have helped to break open clogged arteries and keep people functioning longer. That is really primarily related to heart attack risk — what happens when a coronary artery is plugged up with plaque and causes heart damage.
What there has been an increase in has been heart failure, because many people have been surviving heart attacks but have gone on to develop impaired heart function, and that unfortunately has been on the rise. But the main underlying cause of all of this has been dramatically improved but not eliminated by the measures we discussed — diet, drugs, and coronary artery procedures. Heart disease still remains the leading cause of death. Stroke, also a leading cause of disability, is related to the same underlying processes of plaque buildup in the arteries of the brain.
Why is this the case? Well, to some extent it is inadequate acceptance of treatments that can be used to lower risk. Many people who are candidates for lipid-lowering statin drugs either are not getting them prescribed, are not taking them, or have stopped taking them. But beyond that, there's a more fundamental issue: cholesterol and means of lowering cholesterol are really not the only factors to consider here. There are a number of other very key factors that lead to buildup of cholesterol-containing plaques in the arteries — chief among them being inflammation. We've known for some time that vascular heart disease is in essence an inflammatory condition, and we have yet to identify means of counteracting that effect that are generally available in clinical practice.
The other major issue, which cuts across a whole lot of diseases beyond heart disease, is of course overweight and obesity — probably the biggest public health problem we're facing related to heart disease risk. Forty percent of the population or more being obese, thirty percent being overweight — so seventy percent of the US population is carrying around excess body weight. And when that body weight is around the middle, in the part of the abdomen called the visceral fat region, that sets off a whole variety of effects: inflammation being one of them, but also metabolic changes, chief among those being insulin resistance and predisposition to diabetes. Those are a whole set of factors that have not been well controlled in the population. Although we now have some great drug tools available that have helped reduce obesity in many individuals, those are still not generally used. They're expensive. They're not always accessible to patients. That represents, in my view, one of the major factors that has led to failure to improve heart disease risk any more than has already occurred.
Mike Haney: Have you seen any studies about cardiovascular disease impact from people taking GLP-1s yet?
Ronald Krauss: I have not. It certainly would be predicted to be beneficial for obvious reasons, but I'm not aware of any. I mean, there are ongoing studies, that's for sure. There's a lot going on in this area, but I haven't really seen any outcome data as yet.
Beyond HDL and LDL: the lipoprotein story you weren't told
Mike Haney: I want to ask about what's right and what's wrong about the general public narrative on cholesterol. Most middle-aged people who aren't paying close attention to health information would say: something in the diet — maybe dietary cholesterol, maybe saturated fat, maybe carbohydrates — causes high cholesterol, which leads to plaque buildup in the arteries, which leads to a stroke or heart attack. What's right and what's wrong with that causative narrative?
Ronald Krauss: We've been talking about cholesterol as a generic term that is really one of the standard laboratory tests we use. But when it comes to the mechanisms by which cholesterol impacts heart disease risk, we have to start talking about lipoproteins, not just cholesterol.
There are packages in the blood that contain not just cholesterol but proteins and other fats — they circulate in the form of particles. And it's those particles containing cholesterol that wind up in the artery wall and lead to plaque buildup. There's a whole variety of those particles. Cholesterol doesn't come in just one form; it comes in multiple lipoprotein forms. The most widely measured is low-density lipoprotein, or LDL, which is an established risk factor for heart disease — but it's not the only one. And beyond that, LDL itself comes in different forms, and that's something I've been deeply involved with. There has been increasing clinical awareness that there are some types of LDL particles that appear to be quite strongly associated with heart disease risk and others that are less strongly associated. That's an area that has regrettably not been fully understood or implemented in clinical practice.
There are also other lipoprotein particles to consider — those that contain not just cholesterol but triglyceride in particular, which can also damage the arteries. Those are influenced to a large extent by diet, by overweight, by physical inactivity. This form of lipoprotein is called remnant lipoproteins. These are partially broken-down lipoprotein particles that have acquired serious pathologic properties, and they are not routinely measured in clinical practice. That's a gap we're trying to fill by developing more comprehensive tests — not just for LDL and its different forms, but also to include these other lipoprotein particles so we can get a more comprehensive assessment of risk in individuals.
Carbohydrates — and processed grains and sugars in particular — have a much more important effect on the forms of lipoproteins most strongly associated with risk than saturated fat does. I'm glad to see the emphasis is hopefully going to be shifting more towards that component of diet and not so much focusing exclusively on saturated fat.
Mike Haney: Maybe this is a good point to do a little physiology 101. You mentioned cholesterol as a package that can also include triglyceride, and that we have these different densities — we've heard of LDL and HDL, but there's also VLDL and intermediate density. Maybe just explain the high-level physiology of how cholesterol gets synthesized, how it gets packaged, how it moves through the body, and how we end up with these different forms and particle sizes.
Ronald Krauss: The liver is where all of the metabolism happens that leads to the production of lipoproteins. The liver synthesizes cholesterol, triglyceride, and proteins that are secreted into the bloodstream as lipoprotein particles. The primary secretory product — the one that starts off the metabolic reaction that leads to LDL — is called VLDL, very low-density lipoproteins. These are primarily triglyceride-rich and contain cholesterol and some other proteins. The major protein that characterizes VLDL as well as its metabolic products is called apoprotein B, or ApoB, and there is one ApoB molecule on each lipoprotein particle.
These VLDL are then metabolized by enzymes called lipases that break down the triglyceride, releasing it into other tissues such as adipose tissue and muscle as fatty acids used for energy or storage. As that triglyceride is removed, we see the formation of what I mentioned earlier — remnant lipoproteins. These remnant particles become smaller and smaller, and various other steps transform those remnants into LDL. So LDL particles are the end result of this pathway starting from VLDL released by the liver, with an intermediate density stage called IDL along the way.
The LDL can come in different forms depending on the nature of the VLDL that was secreted. If there's more VLDL secreted, if there's more triglyceride packaged in these particles, that tends — interestingly — to form actually smaller LDL down the line, because the triglyceride gets removed and the particle shrinks to a very small LDL. Those small LDL have properties that render them particularly toxic to the arteries — not just their cholesterol content, which is not particularly high, but other properties which include the ability to bind to the artery wall, to promote inflammation, which is a key factor in this whole disease process, and ultimately to promote plaque breakdown and rupture, which is the final step leading to a heart attack.
Then there's a separate pathway that involves release of a different, larger form of LDL, which is less damaging to the arteries. That defines really two parallel pathways by which lipoproteins are produced in the blood that are related to heart disease risk.
HDL — high-density lipoproteins — come into play through a similar synthetic process. The liver and intestine make HDL. These are very small cholesterol-containing particles completely different from VLDL, IDL, and LDL. The major protein in HDL is called ApoA-1, and that has the property of being able to extract cholesterol from tissues and take it back to the liver — that's called reverse cholesterol transport. So HDL functions as a kind of cleanup mechanism that tends to balance cholesterol that may be coming out in excess through these other lipoproteins into tissues or the excess cholesterol that may be synthesized. Cholesterol is actually synthesized in all the tissues in the body. So it's not just coming from the blood, and HDL is capable of sensing when there's too much cholesterol in those tissues and bringing it back to the liver. That's a good function of HDL.
However, there has been some confusion — which I think is now becoming resolved — about whether having high levels of HDL is a protective factor. While we know that HDL has protective mechanisms, we now know that raising HDL to high levels, which can be done through various drug treatments, is not always beneficial. The bottom line from a variety of lines of evidence, including clinical trials aimed at raising HDL, genetic markers of HDL levels, and clinical observational studies, is all pointing toward moving away from considering raising HDL to be something that is always beneficial. HDL has good properties, but raising HDL is not necessarily a helpful procedure — as opposed to lowering levels of the ApoB-containing particles, particularly remnant lipoproteins and small LDL, which clearly does contribute to a reduced cardiovascular risk profile.
"Small LDL have properties that render them particularly toxic to the arteries — not just their cholesterol content, but other properties which include the ability to bind to the artery wall, to promote inflammation, and ultimately to promote plaque breakdown and rupture." — Dr. Ronald Krauss
LP(a): the silent risk factor affecting up to a third of the population
Mike Haney: Since we've mentioned a lot of other terms here, we should probably include LP little a. Can you tell me where that fits into the story?
Ronald Krauss: LP(a) is a completely different lipoprotein particle. Although it consists of an LDL particle, it has been modified by the attachment of another protein to ApoB, and that protein is called apo(a). That combined particle — the LDL plus apo(a) — is what forms what we call LP(a). It is produced through a completely different set of pathways that are largely determined by genetics.
High levels are really remarkably prevalent. It's been estimated that perhaps up to a third of the population carries a genetic predisposition to high levels of LP(a), which has been clearly shown to be related to risk of heart disease and stroke, and also influences the aortic valve and can cause aortic valve problems. So it's a very bad player that is present in a really high proportion of the population.
Until recently it's been generally set aside in the clinic because there have not been tools available for lowering LP(a), given its strong genetic influence. However, there are now very far along medications — treatments that can turn down the production of LP(a) at the gene level — that appear to be quite effective and hopefully will be shown to reduce heart disease risk. I've been talking about LP(a) for 40 years, ever since it was originally discovered, but it remained kind of a well-kept secret until more recently. And I think we're going to be hearing much more about it.
One of the reasons for measuring LP(a), even if we don't have treatments available, is to identify people at high risk for heart disease before disease develops, so that we can intervene more effectively by taking measures that can lower risk by reducing LDL levels and other heart disease risk factors. Learning about high LP(a) can be quite effective in guiding treatment strategies for prevention, and also for identifying family members who might consider themselves healthy and low risk but who may have inherited the gene. Picking that up at an early age is something we can also consider a worthwhile goal.
Mike Haney: Is the increased risk from high LP(a) through independent mechanisms — like what it can do to the aortic valve — or is it inserting itself into the causal story with LDL? Why do we have increased risk if we have LP(a)?
Ronald Krauss: I consider LP(a) to be a multiplier of risk. It does not operate through the pathways we just talked about — the VLDL, IDL, LDL pathways. It's a completely separate pathway that again starts in the liver but does not intersect with LDL metabolism. However, it does have similar effects in the arteries — just like LDL remnants can deliver toxic lipids into the arteries, LP(a) can deliver cholesterol into the arteries much as those lipoproteins do.
But beyond that effect, it has other properties beyond those of the LDL particle that promote even more inflammation, and also clotting — thrombosis — is promoted by LP(a). So it has sort of a triple-whammy effect: delivering cholesterol and lipids to the artery, stimulating inflammation, and promoting thrombosis. It's really a bad player. On a particle basis, it's actually as toxic or more toxic than these other lipoproteins.
Mike Haney: Yeah, that makes sense because I feel like the clinical interpretation of this is usually if you have that high LPA genetically, then we're going to take your other cholesterol markers more seriously. And I think that idea of it as a risk multiplier then definitely makes sense.
The triglyceride-carbohydrate connection: why carbs may matter more than saturated fat
Mike Haney: Coming back to that physiological story of how lipoproteins are formed — what I'm hearing is that starting with a VLDL particle that has a high level of triglyceride in it, somewhat counterintuitively, having more triglyceride in that original particle is ultimately going to lead to the small, dense LDL that are the dangerous ones we care most about. And that the sometimes-called "large fluffy" LDLs actually come from having less triglyceride. Is that where the impact of carbohydrate comes in — because excess carbohydrate can lead to fat buildup and increased triglycerides — and why having high triglycerides is also a factor in heart disease risk?
Ronald Krauss: High triglyceride was shown to be a risk factor for heart disease even before cholesterol was — this goes back to the 1950s — but it sort of fell to the wayside because the focus switched to cholesterol. Not inappropriately — the LDL story is important as well. But the triglyceride axis is related to this pathway that involves the production of these triglyceride-rich VLDL lipoproteins from the liver. And that process is stimulated by dietary carbohydrates — sugars in particular, but carbohydrates in general — that promote production of fatty acids in the liver that are packaged into triglycerides. That's how triglycerides are formed. So the more carbohydrates one consumes, the more of these triglyceride-rich VLDL are produced in the liver and ultimately secreted.
That is in my view a key underlying factor that is responsible for the relationship of triglyceride to heart disease — the production of these particles, which as we talked about undergo progressive shrinkage. There are also factors produced in conjunction with triglyceride that can actually slow down that clearance process so that the particles hang around longer. And the longer these particles are circulating in the blood, the more likely they are to encounter the arteries.
What I would call the residence time — the amount of time that such particles are present in the circulation — is a key determinant of heart disease risk. Factors such as exercise and leanness can promote rapid clearance of these lipoprotein particles so they don't stay around in the blood. In situations where the process is slowed down, triglyceride levels remain higher in the blood, and slowly those particles get broken down further and metabolized to smaller LDL. And all of this represents a pathway that exposes the artery to these bad actors for long periods of time.
It's actually been shown that small LDL tend to hang around in circulation longer — they are less able to be swept out of the bloodstream by the liver because they interact less effectively with LDL receptors. So that whole pathway starting with large, triglyceride-rich VLDL represents a pathway that exposes the arteries to all of these detrimental products down the line. And that's one of the reasons that triglyceride is such an important component of risk. We can do a lot to reduce that impact through limiting carbohydrate intake, weight loss, and exercise — all of that tends to reduce the impact of this pathway.
"The residence time — the amount of time that lipoprotein particles are present in the circulation — is a key determinant of heart disease risk. Factors such as exercise and leanness can promote rapid clearance so they don't stay around in the blood." — Dr. Ronald Krauss
Pattern A vs. Pattern B: why two people with the same LDL can have very different risk
Mike Haney: I want to hang on particle size for a while because I know you've done a lot of pioneering work in that space. If I've got a high LDL number, what's the amount of individual variance in how much of that LDL is small versus big? In other words, one person with an LDL of 200 might have a very different risk profile than somebody else with an LDL of 200.
Ronald Krauss: One of the first observations I made in this arena was to show that individuals can generally be classified into two categories if one looks at the LDL particle sizes. A group of individuals who tend to have primarily larger LDL — we call those individuals pattern A. And a second very distinct group that has a predominance of smaller LDL — those are pattern B. Those are metabolically defined subgroups of the population that are programmed both genetically and also by lifestyle factors to have either primarily the larger or smaller LDL.
Individuals with large LDL still have some small LDL — they just have a greater amount of the larger form. So it's the relative proportion of large LDL that determines phenotype A, and the relative proportion of small LDL that determines phenotype B. There are no fixed ratios that we can identify. We really just look at that profile as an index of those predominant forms of LDL in the blood.
But in terms of impacting heart disease risk, it's not just whether the LDL are larger or smaller — it's the amounts. Rather than trying to predict the amounts from looking at the size, one can actually measure the amounts of these particles in the blood using a couple of tests available through major clinical labs that can determine, within a given level of total LDL, first the LDL particle count — the total number of LDL particles — and second the breakdown: what is the concentration of larger LDL particles and what's the concentration of smaller LDL particles?
I'd have to say there's no such thing as a good LDL particle. Large LDL particles are not totally benign — if there are too many of them, they can also increase heart disease risk. But the relative risk between the larger and the smaller particles clearly tips towards the smaller particles. That's where we try to lower those levels through dietary measures, weight loss, exercise, and of course medication where necessary, to try to reverse that profile. And we can convert people from the B form to the A form — get rid of those small LDL — by those interventions. And we do have the labs that do these tests do have target levels. We don't — unfortunately there hasn't been a consensus yet on exactly what those targets should be. This is still a field that would benefit from more research to be able to get better handles, particularly in multiple populations. We just don't have a lot of data to be able to pinpoint exactly what the target level should be. We have some general guidelines, and in the case of these LDLs, we already know that lower is better. So we try to reduce those levels as much as we can in a helpful way, and try to aim towards what the laboratories consider to be the optimal endpoint.
Mike Haney: That understanding of particle count comes back to why we want more folks to get an ApoB, right? Because ApoB is going to be your particle count, whereas your cholesterol number is telling you the total amount of cholesterol — which is less revealing.
Ronald Krauss: Right. ApoB does provide a measure of all of the lipoprotein particles associated with heart disease risk, so it's a first step in my view. High levels of ApoB are certainly more informative than LDL cholesterol because they represent the particles that actually wind up affecting the arteries. But within ApoB, there are some particles that are less important than others. And so that's why one can take the next step beyond ApoB — measure the particles themselves — which in my view is a more logical second step, because we can then determine what steps we should take.
For example, a high level of ApoB can be associated with large particles, and if those levels are high enough, that can certainly be a serious risk factor for heart disease. But in those cases, we may use diets that are more limited in saturated fat, which affects those larger particles more than the smaller ones. If we find individuals who have high levels of ApoB due to increased levels of small LDL, that's where we would focus more on carbohydrate limitation and weight loss, and less unsaturated fat, which has minimal effects on most particles. So learning which particle types contribute to high ApoB can help lead toward individualized, more precision-oriented treatment approaches that are focused on the specific forms of lipoproteins present in that individual.
The diagnostic ladder: what tests to get and when to go further
Mike Haney: In my experience, everybody's going to get their basic cholesterol panel. ApoB I think is a little bit easier to get — it feels like there's a little bit more awareness, it's a pretty cheap test, it's pretty common, it's pretty standard. Quest and LabCorp both do it, so that's a little easier to add on. LP(a) I think similarly, you know, you can ask for an LP(a) because it's largely genetically determined. More or less, if you get it once, that's fine — you've got it now, you kind of know what your LP(a) picture is. Particle size feels a little bit more esoteric in terms of just the testing landscape. How common is particle size testing, and how useful and accurate and standardized is it?
Ronald Krauss: This is an area that has been evolving. Right now there are really just two established procedures for measuring particle numbers and the subtypes of LDL size. One involves nuclear magnetic resonance, and another involves a technique called ion mobility. These are different measurement principles, and they have unfortunately not established common ground between those two tests in terms of what the target levels should be, or even what the measurements themselves indicate in terms of which subfractions are elevated. There generally is concordance between those two tests, but it's not perfect.
Physicians who order these tests have to be aware of these issues, and there have certainly been educational efforts to try to improve understanding of those tests. But it's a very small minority of clinicians who are really aware of this or choose to use these measurements. And that's where ApoB is more attractive — it's something people can understand more easily, it's more generally available, and it's well standardized. The particle tests unfortunately are not at that level. But that doesn't mean they don't have value if one is sufficiently familiar with what the measurements signify and how they can be used clinically. It takes more education to understand, and that's probably more than most primary care physicians care to try to implement, so uptake has been relatively limited.
Mike Haney: Can I infer anything about my relative particle size ratio by looking at my ApoB and my LDL number — any discordance between those two numbers?
Ronald Krauss: Generally yes. The ratio of cholesterol to ApoB in small LDL is low — small LDL have less cholesterol per particle. So one can have individuals who have high levels of ApoB but normal or even low levels of LDL cholesterol, and it's reasonable to infer that they have high levels of small LDL particles. Conversely, individuals in whom the ApoB level and the LDL cholesterol level are more concordant — if both are elevated to a comparable extent — that's a sign of larger LDL. But trying to do mathematical ratios of ApoB to LDL cholesterol has not really been useful. You can get a general orientation between those two categories, but the ratio is really not sufficient to pinpoint the numbers of particles.
Mike Haney: So how much can I learn from just my standard panel? If my LDL is in the 150 to 200 range — not crazy off the charts, but high enough that my primary care might say let's think about a statin — is that enough to assess my risk, or should I go further into ApoB or even particle size?
Ronald Krauss: Current practice really starts with measuring LDL cholesterol, and ApoB unfortunately has not yet risen to the level of the preferred measurement. ApoB is considered optional. So most individuals will start with an LDL level, and if the LDL cholesterol level is high enough, that would be sufficient to categorize them at high risk — for example, individuals with LDL cholesterols in the high hundreds approaching 200 are often affected with a genetic form of LDL elevation called familial hypercholesterolemia, and those individuals are at significant risk of heart disease where further analysis may not be that informative.
Where the more defined measurements come into play — in my view and in my own practice as well as among my colleagues in lipidology — is when the lipid levels are more in the borderline range. And that is by far the most common situation for people with heart disease or at risk for heart disease. They don't have super high LDL levels. Triglyceride levels may be on the borderline — I like to see triglyceride levels below 100, and if they're closer to 150 you start to think about factors that might affect LDL metabolism as we just talked about. In those individuals, simply looking at LDL cholesterol is not sufficient. That's where the underlying form of LDL in the blood, and the other lipoprotein measurements related to triglyceride metabolism, all come into play in a way that could be much more clearly shown by an ApoB measurement — and in my view, particle count measurements as the next step down the line.
It's those borderline situations — particularly if there's a family history that would heighten the likelihood that something genetic might be affecting the particle profile not revealed by the LDL level — where those measurements become most useful.
Mike Haney: And how much, when you're trying to understand that clinical picture, are you looking at HDL, triglycerides, and LP(a)?
Ronald Krauss: I measure LP(a) in everybody who I consider at high risk for heart disease. It actually shows up in early childhood because it's genetic — if it's high, it stays high throughout life. However, in some individuals there are about 40 different genetic variants of LP(a) in the blood, and some of those variants can fluctuate. So I usually measure it twice just to be sure if it's high the first time. And I do that in everyone because it's just such a prevalent condition, and it's a silent condition that you won't learn about unless you measure the test.
Metabolic syndrome: when the whole picture matters more than any single number
Mike Haney: Maybe this is a good bridge into metabolic syndrome and the five markers that together give a better indication of risk. I think what I'm trying to untangle for people is: you go get a cholesterol panel, your LDL is a little high, other things seem okay, you're not wildly obese — maybe don't worry about it. And yet something like 93 or 94% of people have at least one of those five metabolic syndrome markers out of whack. At what point, and what combination of those factors together, does the risk level start to really increase?
Ronald Krauss: I was involved with the original panel that set the criteria for metabolic syndrome. It's present in well over a third of the population, probably higher now. It's defined as having three or more of five factors: high triglyceride — greater than 150; low HDL, which tends to correlate with high triglyceride and is part of the reason low HDL is associated with heart disease; increased waist circumference; insulin resistance and predisposition to diabetes — which many consider to be the most important factor; and high blood pressure.
Having three or more of those factors qualifies you as at risk for heart disease. Each one independently is a risk factor in its own right, but the combination tends to amplify that risk. And that combination — that metabolic mix — is something that comes along with the territory when one is overweight or obese. That increased abdominal visceral fat tends to expose the risk for metabolic syndrome. Almost everybody in the population is genetically susceptible to this. There are people who are resistant, but for the most part, if you gain enough weight or eat enough sugar, you are likely to start exposing features of metabolic syndrome.
I don't think you can point to any single one as being more important than the others. Among those, however, the one that falls off to the side in terms of therapeutic implications is low HDL. It's helpful to get triglyceride levels lower, get blood pressure lower, get body weight lower, improve insulin effectiveness — but raising HDL has not been proven to be beneficial. So it's a marker that helps define the metabolic syndrome and the risk associated with it, but it's not one we consider a therapeutic target.
"Almost everybody in the population is genetically susceptible to metabolic syndrome. For the most part, if you gain enough weight or eat enough sugar, you are likely to start exposing features of metabolic syndrome." — Dr. Ronald Krauss
Saturated fat: what the standard advice gets wrong
Mike Haney: One lifestyle thing I really wanted to touch on briefly is saturated fat — the kind of standard story of: you have high LDL, cut your saturated fat. There's a study I cite often, I think it was a 2015 RCT in which they cut the amount of saturated fat and saw everything from a 20% reduction in LDL to a 40% increase in LDL from the same intervention in 300 people. There does seem to be a lot of variance in how the saturated fat lever impacts LDL. Why do you think that is?
Ronald Krauss: Saturated fat as an entity is just like saying cholesterol is one thing — saturated fat is not one thing. Saturated fat is really just one component of foods, and the form in which saturated fat appears in those foods can be quite as important as the amount of saturated fat itself.
One of the things that has emerged with more study — some of which I've been involved with — is that saturated fat is the main fat in animal products, the main forms being dairy and meat. Saturated fat in dairy is not necessarily associated with high heart disease risk. Saturated fat in cheese is not necessarily associated with heart disease risk. Saturated fat in red meat — maybe, but there are other factors in red meat beyond saturated fat that could be responsible for risk. So focusing exclusively on saturated fat is missing the point that it's really the food that contains the saturated fat that matters, and it's also the other components of those foods that can be considered important for risk.
I've been relatively unenthusiastic about using any kind of saturated fat index as a measure of what we should be doing with diet. It's about reducing the foods that raise LDL cholesterol in any given patient — and this brings up the factor that there's quite a bit of individual variation in response to foods containing saturated fat. Some people are unresponsive, some people go one way, other people go the other way. We've studied that as well. It has created an unnecessary amount of confusion as opposed to more simplified advice, which is to emphasize foods that tend to have lower saturated fat — plant-based foods in particular — and to be more careful about processed meats especially, which may have adverse effects on risk that are partly related to saturated fat but have other factors involved as well.
Mike Haney: For people trying to translate all of this into practical action — I've heard you describe a sort of heart-healthy diet that comes back to what's broadly called Mediterranean, or maybe more generically: just stop eating processed food and cut out so much refined sugar.
Ronald Krauss: The other point regarding the saturated fat recommendations that I wanted to emphasize is that it's what one substitutes when one reduces saturated fat that makes a huge difference. Foods that are rich in unsaturated fat — olive oil being monounsaturated, polyunsaturated from other sources, nuts, plant oils — can have beneficial effects. If one substitutes carbohydrates for saturated fat, for the reasons we talked about earlier, that can push people in the wrong direction.
So I think it's the benefit of substituting healthful fats and healthful foods for those that are higher in saturated fat that should guide the advice for the patient with high cholesterol. If I have a patient with high LDL, particularly if they have the larger LDL particles that are more sensitive to foods containing saturated fat, I do advise them to limit their intake. But the effect on average is relatively modest compared with statin drugs — one can get lowering of as much as 20% on a very strict low-saturated-fat diet, but generally it's much harder to achieve that, and the effect can vary greatly among individuals. But it's always worth a try.
Mike Haney: Well, I think that's a very good place to end it here. So much of your work is so revealing, Dr. Krauss. We really appreciate you taking the time to chat with us today.
Ronald Krauss: Happy to do that. It's great talking with you.
This article is based on a conversation with Dr. Ronald Krauss, Senior Scientist and Director of Atherosclerosis Research at Children's Hospital Oakland Research Institute and Professor of Medicine at UCSF.
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