What Cholesterol Is and Why We Measure It — Four Lines on a Blood Test, and the Packages They Name

Four Lines

When you open your health checkup report, four lines sit side by side in a single box. Each line has an unfamiliar name attached to it, with a single number written next to it. An arrow is attached next to some lines.

What most people know about this box is just one sentence: that one is bad cholesterol and one is good cholesterol. Beyond that, almost nobody tells you, and your body does not tell you either. A state of elevated fat components in the blood progresses without pain, frequently remaining undiagnosed (PMID 37226967). Therefore, a single sheet of paper is the only news you get.

To write down one answer in advance, three of the four lines are values counting the same single thing in three different ways. This article starts from what that single thing is, and proceeds in turn to what each of the four lines measures and what "high" means. Unfamiliar terms are explained right where they appear.

The Building Blocks the Body Makes Itself

Cholesterol is an oily, water-insoluble material that animal bodies use to build cell membranes, hormones, and bile. First, it is an essential component of the membranes surrounding cells, and cells need it to maintain their proper functions (PMID 41238438). It also serves as the foundation for making steroid hormones and vitamin D, and is used to transmit signals that help the body grow and take its proper shape (PMID 41062796). Cholesterol is a component the body absolutely must have.

Bile is a digestive fluid, also known as gall, that helps digest fatty foods. One of the components inside bile has a separate name. Bile acids are substances the body makes by trimming down cholesterol in the liver and sending it out to the intestines. Some of the bile acids that reach the intestines leave the body together with stool. Therefore, bile acids are also an exit route through which cholesterol escapes the body.

Moreover, the body makes cholesterol itself. The total amount of cholesterol in the body is determined by four interlocking factors: making new cholesterol, absorbing it from the intestines, converting it into other substances like bile acids, and expelling it from the body (PMID 41062796). Not all of the cholesterol we eat enters the body. The human gut absorbs 34 to 57 percent of the cholesterol contained in food, and that proportion varies depending on the amount eaten and the diet (PMID 2184845).

Therefore, the cholesterol in your blood is not simply the sum total of what you ate yesterday. It is the result of what the body has made, absorbed, converted, and expelled. How food ties into these numbers is not the subject of this article, but is covered in The Mediterranean Diet Paradox — Is Fat the Enemy of the Heart, or Essential to Health? (/articles/mediterranean-diet-fat-paradox).

Cholesterol is a material that the body makes and uses itself, and the amount in the blood is the result of a balance between production, absorption, and excretion.

Oil Travels in Packages

If you pour water into a cup and drop in a spoon of oil, no matter how much you stir, the oil gathers back at the top a moment later. Blood is mostly water, and cholesterol does not dissolve in water. What the liver makes needs to be sent all the way to the cells in the leg muscles, and the path is entirely water.

The body’s solution is packaging. A lipoprotein is a spherical package that puts oil on the inside and wraps it in a water-friendly shell, in order to transport oil—which does not mix with water—through the blood, which is water. Triglycerides and cholesterol go on the inside. The outside is enveloped by proteins and molecules that are comfortable with both water and oil (PMID 9785050).

A triglyceride is an oil that the body transports to use as energy or to store, and it is cargo that travels loaded together in the same package as cholesterol. Among the four lines on a health checkup sheet, the triglyceride line is the only one that is not cholesterol.

Now we will follow one package that has left the liver. The liver sends out a package loaded full of triglycerides into the blood. This package unloads triglycerides as it passes through muscle and fat tissue, becoming an intermediate package. The liver takes some of them back. The rest changes one more time to become a package with cholesterol left as its main cargo (PMID 35963623).

LDL is a lipoprotein that is left over after the package sent out by the liver unloads its triglycerides, and whose main cargo has become cholesterol. There are also packages that start from the intestine. These packages go out loaded with the oil you ate, and are the same up to the point of unloading triglycerides into muscle and fat tissue. However, the remaining package does not become LDL and is taken back by the liver (PMID 35963623).

There are also packages that work in the opposite direction. HDL is a lipoprotein that the liver and intestine newly make and send out, which picks up and loads cholesterol from cells. It is a package that goes out empty and sweeps up cholesterol, taking the collected cholesterol back to the liver or passing it on to other packages (PMID 35963623). The L and H in the two names stand for low and high density of the package. Because protein is heavier than oil, packages with a higher proportion of protein have a higher density.

LDL and HDL are types of packages, and the cholesterol carried by both packages is the same substance. The LDL line and HDL line on the checkup sheet are amounts counted by dividing which package the cholesterol is loaded onto.

And this amount is not the same as the number of packages. This is because the amount of cholesterol loaded onto a single package varies (PMID 34677405). The same amount of cargo can arrive packed in a single package, or it can arrive divided among three. The two lines on the checkup sheet measure the weight of the cargo, and do not count the number of packages.

Oil travels in packages, LDL and HDL are the names of the packages, and the checkup sheet measures the cargo inside the packages.

When Those Packages Pile Up on the Artery Wall

Atherosclerosis is a disease where fat and cells build up inside the artery wall, forming a lump that narrows the space. Unlike grime settling inside a pipe, the lump grows inside the wall of the pipe itself. Plaque is the lump formed right inside the artery wall in this way. The disease takes the form of these lumps piling up to block the vessel and reduce the flow of blood passing through (PMID 15052339).

Atherosclerosis is the main cause of heart disease and stroke. In Westernized societies, about 50% of all deaths have this disease at their root (PMID 11001066). It begins in childhood. Left untouched, it progresses over a lifetime, sometimes worsening rapidly (PMID 39043480).

What gets inside the wall is the first question of this disease. Cholesterol can only enter the artery wall carried inside packages (PMID 31642874). Every package that heads toward the wall, including LDL, carries a single label. Apolipoprotein B is a protein attached exactly once to every single package that piles up on the artery wall. It is like a shipping label attached to each individual box. Thanks to this one-to-one relationship, measuring the amount of apolipoprotein B in the blood directly counts the number of packages (PMID 34677405).

Why the number matters is answered by a 2019 review using an explanation different from the traditional model (PMID 31642874). The traditional model assumed that the weight of cholesterol carried in blood packages determines how much piles up on the wall. According to this review, the amount of cholesterol that accumulates inside the wall is determined by the number of packages trapped inside. And the number of packages entering the wall is mainly determined by the number of packages circulating inside the vessel.

Differences in package size offset each other. Smaller packages with less cholesterol get trapped inside the wall more easily, while larger packages with more cholesterol drop off more when a single one gets trapped. Therefore, barring a few exceptions, these packages cause disease to a similar degree per count, which is the conclusion of this review (PMID 31642874). By this explanation, the number closer to the amount that will pile up on the wall is the count of packages rather than the weight of their cargo.

What happens after they are trapped is the problem. The disease begins as immune cells tasked with cleanup eat away at the LDL. However, the LDL in the blood is not eaten as it is; it must first be modified (PMID 15052339). Immune cells that have eaten modified LDL become packed with fat and swell up like foam (PMID 21226274).

The disease begins as oxidized LDL builds up in the inner layer of the artery wall. As the disease progresses, the accumulated lump ruptures, and blood clots on top of it. When that mass completely blocks the flow, it results in a myocardial infarction—where blood is cut off to the heart muscle—or a stroke (PMID 33014272). Atherosclerosis is not just degeneration that naturally occurs with age, but a long-running chronic inflammatory state, and the rupture of the lump combined with the blood clot on top turns it into a sudden event (PMID 11001066).

This is why the LDL line is looked at separately. One short review notes that LDL cholesterol goes beyond being a risk factor that accompanies the disease to being the causative agent of this disease. Because there is no atherosclerosis without LDL cholesterol, the progression of the disease can be altered and even reversed. However, that article simply states a conclusion without presenting evidence separately (PMID 39043480).

There are also materials with a different texture of evidence. Some people are born with genetic variations that make LDL cholesterol slightly lower throughout their lives. Who receives this variation is randomized by nature at birth. Therefore, comparing people with and without this variation allows us to see what happens to individuals whose LDL was low for a lifetime (PMID 23083789).

A 2012 meta-analysis—meaning a study that combined and re-analyzed multiple studies—made this comparison. Gathering studies covering nine genetic variations, they analyzed data from a total of 312,321 people combining those with and without the variations (PMID 23083789). The disease in question is coronary heart disease, which is a condition where the arteries supplying blood to the heart muscle narrow or become blocked.

Having an LDL cholesterol level lower by 1 mmol/L (38.7 mg/dL) was associated with a 54.5% lower risk of coronary heart disease (PMID 23083789). Accounting for random fluctuation, the likely range where this value lies—that is, the 95% confidence interval—was 48.8% to 59.5%. This magnitude is 3 times larger than what has been observed when lowering it by the same amount with medication late in life (PMID 23083789). This means that being born with naturally low levels for a lifetime is not the same as starting to lower them in middle age.

Cholesterol enters the wall only when carried in packages, the amount that enters follows the number of packages, and the moment the accumulated lump ruptures, the disease becomes an event.

The Words "Good" and "Bad"

A person leaving the clinic with a health checkup report usually takes home two sentences: LDL is bad, HDL is good. Based on what we saw earlier, we can fix two parts of these two sentences. First, there are no separate substances called good cholesterol and bad cholesterol; what differs are the packages. Second, the line on the checkup report is the weight of the cargo, so it can conflict with the number of packages (PMID 34677405).

The third place to fix is "HDL is good." This is the area that has been shaken the most over the past 20 years, and the evidence for the "good" side was not as solid as people thought.

Let's start with what HDL is believed to do. Reverse cholesterol transport is the pathway that gathers cholesterol left over in cells throughout the body, returns it to the liver, and sends it out of the body. HDL is the delivery vehicle on this return trip. It was thought that this job was the reason why the more HDL there is in the blood, the less atherosclerosis there is (PMID 1892492).

The observational results also remained consistent for a long time. In studies that measured people first and followed them for several years, the higher the HDL cholesterol, the markedly lower the risk of coronary heart disease. This relationship where one goes up as the other goes down is called an inverse relationship. This inverse relationship was seen even in people whose LDL cholesterol was below 70 mg/dL (PMID 29623098).

Yet raising HDL did not lower the risk. Even when HDL cholesterol was raised through genetic methods, the risk of atherosclerotic cardiovascular disease—heart and blood vessel diseases caused by atherosclerosis—did not decrease. Therefore, the focus of research shifted from the amount of HDL to the function of HDL (PMID 33833449).

A randomized trial is a study that decides who will receive treatment through a lottery and compares them, and it is considered the most reliable method for figuring out causes. The evidence from genetic studies and randomized trials brought into question whether that inverse relationship of HDL cholesterol is a cause-and-effect relationship, in other words, causation (PMID 36337032).

HDL still does several jobs. HDL carries cholesterol and other fat components between various cells, communicates with cells, and even neutralizes toxic substances released by bacteria. The problem is what the checkup report measures. These tasks are performed by the entire HDL package or by specific proteins and fat components carried on it, and they differ from what the cargo measured by HDL cholesterol does. Measuring HDL cholesterol also fails to show how well reverse cholesterol transport is working (PMID 36337032).

As a result, attempts to directly measure what HDL does have continued. One of them is HDL's ability to pull cholesterol out of immune cells. The carotid artery is a thick artery in the neck, and the thicker its wall, the more it is used as a sign that atherosclerosis has progressed. The ability to extract cholesterol showed a strong inverse relationship both with carotid artery wall thickness and with the likelihood of having coronary artery disease. This inverse relationship was independent of HDL cholesterol levels (PMID 29623098).

Based on this, the review suggests that the function of HDL plays a much more important role in protecting arteries than the level of HDL cholesterol in the blood (PMID 29623098). Recent studies also show that these functional indicators and the number of HDL packages predict events like myocardial infarction or stroke better than HDL cholesterol (PMID 36337032).

At the very high end, the direction even reverses. Studies have emerged showing that the relationship between HDL cholesterol and cardiovascular events is closer to a U-shape than a simple inverse relationship (PMID 31049148). This means that the risk goes up whether it is too low or too high.

Low HDL cholesterol was linked to a higher risk of infectious diseases, death from sepsis, diabetes, and chronic kidney disease. This was true in both observational and genetic studies. Conversely, very high levels were linked to a higher risk of age-related macular degeneration (which damages the central vision of the eyes), infectious diseases, and all-cause mortality (PMID 36337032).

The findings so far strongly support the idea that HDL plays an important role in cardiovascular disease. However, it is still not clear how HDL lowers risk. Neither the methods for isolating HDL nor the methods for measuring its function have been standardized (PMID 31145119).

Thus, the conclusion of this section is neither "HDL is good" nor "HDL is useless." A 2023 review concludes like this: to use HDL in clinical practice, HDL cholesterol—an indirect marker that only lets us guess what HDL does—must be replaced with a direct indicator that reflects whether HDL actually plays a causal role in that disease (PMID 36337032).

LDL and HDL are names of packages, and the number on the HDL line does not measure what HDL does.

What Each of the Four Lines on Your Health Checkup Measures

A lipid test is a test that draws blood and measures how much cholesterol and triglycerides are in it. The result sheet has concentrations of cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol in that section, and calculates one more value from them (PMID 37403458). Let us read it line by line from the top.

The first line is the total. Total cholesterol is the sum of all cholesterol carried in every package in your blood. It is the value obtained by putting all the cargo on the scale without asking which package it was carried in.

We saw the HDL and LDL lines earlier. The LDL line has a known limitation. When estimating LDL cholesterol with a standard lipid test, the value becomes inaccurate when a person is not fasting and when triglycerides exceed 200 to 400 mg/dL. The size and number of LDL packages also have limitations as a value representing the risk they carry (PMID 17110236).

Even so, this test has a vast body of evidence, and by providing a simple target called LDL cholesterol, it has reduced coronary heart disease. This 2006 review article considers this test to remain one of the great achievements of the past 50 years. That is, until studies comparing it with an approach targeting the number and size of packages emerge (PMID 17110236).

The triglyceride line was controversial for a long time and was overshadowed by HDL. Packages carrying triglycerides, and the remaining packages after cargo has been unloaded from them, show a consistent relationship with risk. This is true both in studies observing many people and in studies using genetic variants (PMID 33797418).

Those remaining packages are smaller than 70 to 80 nanometers, so they enter and accumulate in the artery wall. Recent data converges on the idea that these remaining packages, rather than triglycerides themselves, are closer to what actually mediates the risk (PMID 34006350). Therefore, the triglyceride line on your health checkup is closer to a value that measures the packages carrying the fat instead of the fat itself.

The last value is obtained by calculation. Non-HDL cholesterol is total cholesterol minus HDL cholesterol. It is the value obtained by counting all the cholesterol carried by the packages excluding HDL—that is, the packages heading toward the wall—all at once, and is calculated rather than measured separately (PMID 37403458). This is what we meant earlier when we said the first three lines are values counting the same single thing in three ways. Total cholesterol counts all cholesterol combined, while LDL and HDL select and count the packages.

Going without breakfast and having blood drawn has long been the standard. A consensus statement jointly issued by two European societies in 2016 changed that standard. The average difference between values measured 1 to 6 hours after a normal meal and values measured while fasting was not large enough to change clinical judgment, even at its greatest.

Triglycerides increased by 0.3 mmol/L (26 mg/dL). Total cholesterol, LDL, and non-HDL cholesterol each decreased by 0.2 mmol/L (8 mg/dL) (PMID 27122601). HDL cholesterol and apolipoprotein B were not affected by fasting status, and the degree to which both methods predicted cardiovascular disease was similar. Therefore, the consensus statement recommends routinely using non-fasting measurements. It also notes that if non-fasting triglycerides exceed 5 mmol/L (440 mg/dL), re-measuring while fasting can be considered (PMID 27122601).

Guidelines—documents in which professional societies organize and present medical practice methods—are on the same side. The 2018 US guidelines allow non-fasting measurements to simplify tests that follow a patient's progress (PMID 31132793).

There are also tests that count the number of packages instead of the weight of the cargo. This is a test that measures apolipoprotein B, the waybill protein attached one to each package. A 2024 expert consensus statement from the American Society for Preventive Cardiology concludes that apolipoprotein B more accurately reflects the burden accumulating on the artery wall than LDL cholesterol, and is useful in clinical practice when used in addition to a standard lipid test. Even though both values rise and fall together across the population, they can disagree within a single person. When they disagree, the risk generally aligns better with apolipoprotein B or non-HDL cholesterol (PMID 39256087).

However, this line is usually missing from your health checkup sheet. One obstacle keeping this test from taking root in routine clinical practice, despite accumulating evidence, is the lack of consistent guidance on how to interpret and use the results. While LDL cholesterol has clear targets and thresholds that change treatment, apolipoprotein B lacks a consistent target (PMID 38950110).

Guidelines have also split. The 2019 European guidelines concluded that apolipoprotein B is a more accurate marker, while the support in the 2018 US guidelines was limited. Still, both guidelines maintained LDL cholesterol as the primary marker guiding treatment (PMID 33870931). As of 2021, replacing LDL cholesterol in prevention guidelines with apolipoprotein B was judged not to be justified, and the discussion was ongoing (PMID 34677405).

Three of the four lines are values counting the same cholesterol differently, the triglyceride line measures packages indirectly, and the line counting the number of packages is not yet on the health checkup sheet.

What "High" Means

The cutoff for "how high is high" varies from document to document. The 2018 U.S. guidelines and the 2019 European guidelines were published less than a year apart yet differ from each other. According to a 2020 review, the U.S. side weighs the effectiveness and costs of additional drugs together, limiting intensive treatment to those at the highest risk. The European side includes treatment targets for both primary prevention in people who have not yet experienced the disease and secondary prevention in those who already have, thus broadening who is covered.

The same review considers the European recommendations harder to implement given worldwide cost and accessibility constraints (PMID 34327477). Therefore, there is no single answer to "how high is high," and the line is drawn differently for different people and depending on which document drew it.

The 2018 U.S. guidelines start with a risk calculator. A risk calculator is a formula that estimates the likelihood of future heart and blood vessel disease using information like age, blood pressure, and smoking status, and this first sorts people into four risk categories. In primary prevention, a discussion of risk between doctor and patient is strongly recommended before deciding on treatment, and that discussion is especially necessary for people at intermediate risk (PMID 31132793).

For some people, the line is drawn very low. The 2026 U.S. guidelines re-introduced treatment targets and lowered the target values. In patients who already have atherosclerotic cardiovascular disease and are at very high risk, targets of an LDL cholesterol below 55 mg/dL and a non-HDL cholesterol below 85 mg/dL are recommended (PMID 42709273). These numbers are values for people who already have the disease and differ from the baseline for someone picking up a health checkup report for the first time.

The lower end is also debated. A safe absolute minimum cannot be specified. However, for patients at the highest risk—those with widespread atherosclerosis where plaque must be stabilized and reversed—some argue that values as low as 20 mg/dL (0.52 mmol/L) can be justified (PMID 28245773).

In older adults, there is evidence pointing in the opposite direction. A 2016 systematic review—meaning an article that gathered relevant studies comprehensively using a defined method—provides that evidence. It collected 19 cohort studies that followed a group of people for a long time, covering 68,094 general population individuals aged 60 and older (PMID 27292972).

In 16 out of 28 cohorts where total mortality was recorded, an inverse relationship appeared where higher LDL cholesterol corresponded to lower mortality. Of those, 14 were statistically significant, and the remaining cohorts showed no relationship (PMID 27292972). The authors argue that this result does not fit the cholesterol hypothesis that LDL cholesterol causes atherosclerosis, and that it is grounds to reevaluate guidelines recommending lowering LDL with drugs in older adults (PMID 27292972).

This is the result of pooling observational cohorts, and its interpretation runs counter to the genetic variant meta-analysis (PMID 23083789) and the mechanism of wall accumulation (PMID 31642874) seen earlier. However, the populations and outcomes looked at by the two sides differ. The genetic variant side looked at coronary heart disease across all ages, while this review looked at all-cause mortality in those aged 60 and older. This article does not judge which side is right, and only notes the fact that the line for "high" is debated according to age as well.

There is also the clearest example of how the line differs by person. Familial hypercholesterolemia is a genetic disease in which LDL cholesterol is high from birth. Because it is an inherited disease, it is tracked through families. It is estimated to occur in 1 in every 250 people in the general population and is more common among people who developed coronary artery disease at a young age. Furthermore, it is underdiagnosed and undertreated. This means it is detected less often than it actually occurs, and even when found, it receives less treatment than needed (PMID 38599725).

Regarding when and in whom it should be measured, a 2023 review draws a line. Measuring LDL cholesterol in all adults is considered a cornerstone of cardiovascular risk assessment. For screening all children, adolescents, and young adults, more evidence is needed to evaluate the cost-effectiveness. However, if there is a family history of early heart and blood vessel disease or multiple risk factors, targeted measurement can be helpful (PMID 37226967).

The line for "high" is drawn differently depending on the person, document, and age, and what number means what for whom is still actively debated.

Where to Look Next

This is the front porch of reading the four lines. There are several doors this article left open as it passed.

The path these packages ride, which is how the heart circulates blood, is looked at from the beginning in How the Heart Moves Blood — Four Chambers, Four Doors, Two Loops. Two other numbers on the same checkup sheet are covered in What Blood Pressure Measures — Two Numbers, and an Answer That Changes With Where You Measure.

What happens when the bump seen in this article bursts and the blood hardens on top of it to block the tube going to the brain is covered in What a Stroke Actually Is — Blocked, Burst, and the Clock.

How getting better numbers and getting a better person diverge is tackled head-on in Better Numbers, Better Patients? — An Introduction to Surrogate Endpoints. The four lines of this article are a textbook example of that question. How to translate sentences like "risk was 54.5% lower per 1 mmol/L of LDL" into human numbers is answered in What Does "50% Lower Risk" Mean in People? — Reading Relative Risk, Absolute Risk, and NNT.

The debate surrounding what we eat and saturated fat is covered in "The Mediterranean Diet Paradox — Is Fat the Enemy of the Heart, or Essential to Health?", and what coffee does to these numbers is covered in "Coffee and Health — What We Got Wrong, and the Warnings That Still Hold".

What happens if this bump grows in the blood vessels that supply blood to the heart itself continues in What Coronary Artery Disease Is — The Road That Feeds the Heart, Narrowed and Blocked. What cholesterol-lowering drugs actually do is a door this article merely left open and passed by. It has not been written yet.

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• "High-density lipoprotein (HDL) functionality and its relevance to atherosclerotic cardiovascular disease." (2018) — PMID 29623098 — Several prospective epidemiological studies showed a clear inverse relationship between serum HDL-C and coronary heart disease risk, and this was true even when LDL-C was below 70 mg/dL. ⚠️However, recent genetic studies and clinical evidence challenge the long-held dogma that 「higher HDL-C is always beneficial and lower HDL-C is always harmful」. Cholesterol efflux capacity (CEC) from macrophages shows a strong inverse association with both carotid intima-media thickness and angiographic coronary artery disease probability independent of HDL-C levels.
• "High-density lipoproteins, reverse cholesterol transport and atherogenesis." (2021) — PMID 33833449 — Plasma HDL-C concentration shows a negative correlation with ASCVD risk. Because raising plasma HDL-C through genetic approaches does not reduce ASCVD risk, the focus of research has shifted from the quantity of HDL to the function of HDL. While the inverse correlation between macrophage efflux and ASCVD supports the reverse transport model, observations such as the rapid clearance of free HDL cholesterol from plasma within minutes cast doubt on the mechanism.
• "High-density lipoprotein revisited: biological functions and clinical relevance." (2023) — PMID 36337032 — ⚠️Evidence from genetic studies and randomized trials has questioned whether the inverse association of HDL-C is causal. HDL operates like a reusable ferry carrying cholesterol and lipids between cells, performing multiple functions such as cell communication and inactivation of biological hazards like bacterial lipopolysaccharides. These functions are the work of the entire HDL particle or specific proteins and lipids carried by HDL, not the cholesterol cargo measured by HDL-C. HDL-C measurement also fails to reflect the efficiency of reverse transport. Functional metrics such as cholesterol efflux capacity, HDL particle number, and specific HDL proteins predict ASCVD events better than HDL-C. Low HDL-C is associated observationally and genetically with increased risks of infectious disease, sepsis mortality, diabetes, and chronic kidney disease, while conversely, extremely high HDL-C is associated with increased risks of age-related macular degeneration (also genetically), infectious disease, and all-cause mortality. To use HDL clinically, the indirect marker HDL-C must be replaced with direct biomarkers reflecting HDL's causal role in the respective disease.
• "HDL and Reverse Cholesterol Transport Biomarkers." (2019) — PMID 31049148 — Recent studies challenge the premise of an inverse association between HDL-C and cardiovascular events, suggesting a more U-shaped association. Both HDL particle number and cholesterol efflux are inversely associated with the occurrence of cardiovascular events and may be better intervention targets.
• "High-density lipoprotein: our elusive friend." (2019) — PMID 31145119 — Current findings strongly support that HDL plays a significant role in cardiovascular disease, but the mechanism by which HDL mitigates risk remains unclear. A major problem in HDL research is the lack of standardization in both HDL isolation methods and HDL function measurement methods, with different methods yielding discordant results in particle number, size, composition, and function.
• "Lipid Profile and Lipoprotein(a) Testing." (2023) — PMID 37403458 — Measuring cholesterol, triglycerides, HDL-C, and LDL-C concentrations, calculating non-HDL cholesterol concentration, and determining Lp(a) once in a lifetime can quantify lipid-related risk and track treatment efficacy. These blood tests can be performed in the non-fasting state except in special circumstances (particularly hypertriglyceridemia). HDL index (ratio) is an outdated metric.
• "Standard lipid profile." (2006) — PMID 17110236 — The standard lipid profile has an expansive scientific evidence base and has reduced coronary heart disease by providing simple clinical goals focused on LDL cholesterol. ⚠️The limitations involved in 「estimating」 LDL cholesterol are well-known — it becomes inaccurate in the non-fasting state and in people with triglycerides exceeding 200 to 400 mg/dL, and there are also limitations as an accurate measure of the risk carried by LDL particle size and concentration. Nonetheless, the author calls this test one of the great clinical and public health achievements of the past 50 years.
• "Triglycerides and cardiovascular disease." (2021) — PMID 33797418 — The relationship between triglycerides and cardiovascular risk has long been controversial and overshadowed by HDL-C. Epidemiological studies show a distinct relationship between triglyceride-rich lipoproteins, including remnants, and cardiovascular risk, which is most clearly revealed by the excess risk that non-HDL-C captures beyond LDL-C. Mendelian randomization studies using genetic variants linked to triglyceride metabolism also show a consistent relationship.
• "The role of triglycerides in the origin and progression of atherosclerosis." (2021) — PMID 34006350 — Hypertriglyceridemia has been associated with cardiovascular risk for decades, but data suggesting triglyceride-rich lipoproteins as a causal factor for atherosclerosis are recent. The finding that remnant particles (RLPs), the lipolytic products, rather than plasma triglycerides or triglyceride-rich lipoproteins themselves, are the true mediators contributed to explaining the causal relationship. RLPs are below 70 to 80 nm in size, enabling them to enter the arterial wall and accumulate in the subendothelial space, participating in cholesterol deposition in the intima and various inflammatory and apoptotic pathways.
• "Fasting is not routinely required for determination of a lipid profile: … a joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine." (2016) — PMID 27122601 — Joint consensus statement from two European societies. The maximum mean changes 1 to 6 hours after a normal meal were not clinically significant — triglycerides +0.3 mmol/L (26 mg/dL), total cholesterol −0.2 mmol/L (8 mg/dL), LDL-C −0.2 mmol/L (8 mg/dL), calculated remnant cholesterol +0.2 mmol/L (8 mg/dL), and calculated non-HDL-C −0.2 mmol/L (8 mg/dL). HDL-C, apoA1, apoB, and Lp(a) concentrations are not affected by fasting status. Fasting and non-fasting values have similar variability over time and are similar in predicting cardiovascular disease. Therefore, routine use of non-fasting lipid testing is recommended, and fasting blood collection can be considered when non-fasting triglycerides are >5 mmol/L (440 mg/dL).
• "2018 Cholesterol Clinical Practice Guidelines: Synopsis of the 2018 AHA/ACC/Multisociety Cholesterol Guideline." (2019) — PMID 31132793 — Summary of the 2018 US Guidelines. The risk calculator first classifies patients into 4 risk categories, and for individuals at intermediate risk, clinician-patient risk discussion prior to starting statins is strongly recommended. In primary prevention, clinician-patient discussion prior to treatment decisions remains strongly recommended, and in intermediate-risk individuals, risk-enhancing factors and coronary artery calcium testing can aid judgment. To simplify follow-up, non-fasting lipid measurement is permitted.
• "Role of apolipoprotein B in the clinical management of cardiovascular risk in adults: An Expert Clinical Consensus from the National Lipid Association." (2024) — PMID 39256087 — Expert Clinical Consensus from the National Lipid Association. ApoB represents the total concentration of circulating atherogenic lipoprotein particles and more accurately reflects the atherogenic burden of lipoproteins than LDL-C. When used alongside standard lipid profiles, it has clinical value in risk assessment and treatment management. Despite high population-level correlation, in individuals LDL-C and apoB can be discordant, and when discordant, ASCVD risk generally aligns better with apoB or non-HDL-C. Improving accessibility and insurance coverage for apoB testing is urgent.
• "Apolipoprotein B: Bridging the Gap Between Evidence and Clinical Practice." (2024) — PMID 38950110 — Despite data showing that apoB measurement is superior to LDL-C in predicting ASCVD risk, apoB measurement has not been widely adopted into routine clinical practice. One hurdle is the lack of consistent guidance on how clinicians should interpret and apply apoB results. While guidelines have provided clear targets or treatment modification criteria for LDL-C, there are no consistent targets for apoB.
• "Update on apolipoprotein B." (2021) — PMID 33870931 — The 2019 European (ESC/EAS) guidelines concluded that apoB is a more accurate measure of cardiovascular risk than LDL-C or non-HDL-C, whereas the support for apoB in the 2018 US (ACC/AHA) multisociety guidelines was limited. ⚠️Nevertheless, both guidelines maintained LDL-C as the primary metric driving treatment.
• "Same evidence, varying viewpoints: Three questions illustrating important differences between United States and European cholesterol guideline recommendations." (2020) — PMID 34327477 — The 2019 ESC/EAS guidelines were published less than a year after the 2018 AHA/ACC multisociety guidelines, and differences exist between the two. The US guidelines prioritize the added efficacy of non-statin therapies alongside cost implications, restricting intensive treatment to those at the highest ASCVD risk, whereas the European approach incorporates treatment goals into both primary and secondary prevention, widening the target criteria. Considering cost and accessibility constraints in global healthcare, the European recommendations are harder to implement.
• "Top 10 Concepts in Secondary ASCVD Prevention From the 2026 ACC/AHA Dyslipidemia Guideline: What Is New and Why It Matters." (2026) — PMID 42709273 — Summary of secondary prevention from the 2026 US Guidelines. ⚠️In patients with clinical ASCVD who are at very high risk, recommending targets of LDL-C <55 mg/dL and non-HDL-C <85 mg/dL. Reasons remaining for residual risk despite high-intensity statins include delayed treatment intensification, persistent apoB-containing lipoprotein burden, high Lp(a), triglyceride remnant particles, and cardiorenal-metabolic comorbidities.
• "Low-Density Lipoprotein Cholesterol (LDL-C): How Low?" (2017) — PMID 28245773 — There is clinical evidence that therapeutically lowering LDL-C reduces atherosclerotic events. Very low LDL-C is also seen in healthy individuals, such as newborns, those with hypobetalipoproteinemia, and PCSK9 gain-of-function mutants. ⚠️A definitively safe lowest LDL-C level cannot be specified. However, there is discussion that in highest-risk cardiovascular patients with extensive atherosclerosis who require plaque stabilization and regression, values as low as 20 mg/dL (0.52 mmol/L) may be justified.
• "Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review." (2016) — PMID 27292972 — ⚠️A systematic review representing a minority perspective questioning the cholesterol hypothesis. 19 cohort studies, 30 cohorts, and 68,094 individuals aged 60 and older in the general population where LDL-C was evaluated as a risk factor for mortality. An inverse association between LDL-C and all-cause mortality appeared in 16 out of 28 cohorts where all-cause mortality was recorded (14 of which were statistically significant, representing 92% of participants for whom this association was recorded), with no association in the remainder. Cardiovascular mortality showed the lowest LDL-C quartile to be highest in 2 cohorts out of 9, with no association in 7. Author conclusion: These findings do not align with the cholesterol hypothesis and provide a basis for re-evaluating guidelines recommending pharmacological reduction of LDL-C in the elderly.
• "Familial hypercholesterolemia." (2024) — PMID 38599725 — Familial hypercholesterolemia is a common autosomal dominant genetic disorder associated with elevated LDL cholesterol. It is estimated at 1 in 250 individuals in the general population (roughly 5 million estimated in India). The prevalence is higher in young coronary artery disease patients (men under 55, women under 60). It is underdiagnosed and undertreated, making childhood screening and cascade screening of relatives of known patients critically important.