While the benefits of lowering elevated LDL (“bad”) cholesterol are proven, in recent years research has raised fundamental questions about the supposed benefits of increasing HDL (“good”) cholesterol. That’s why official guidelines focus exclusively on lowering LDL cholesterol, which is the main purpose of statin drugs (they raise HDL cholesterol only slightly). Now accumulating research has found that having high HDL cholesterol can sometimes actually promote, rather than prevent, cardiovascular disease.
First a note: HDL (high-density lipoprotein) and LDL (low-density lipoprotein) are complex packages of lipids and proteins that transport cholesterol in the bloodstream. Standard blood tests measure only the cholesterol carried by these packages, and the results are reported as HDL cholesterol (HDL-C) or LDL cholesterol (LDL-C). But HDL and LDL are a lot more than just the cholesterol they carry.
Too much of a good thing?
We don’t usually report on unpublished research, but a study from Emory University in Atlanta, presented at a cardiology conference in late 2018, got lots of media attention, notably in a health column in the New York Times, titled “HDL Cholesterol: Too Much of a Good Thing?” The researchers followed more than 5,900 people for almost four years and found that, after controlling for a variety of factors, those with HDL-C levels of 41 to 60 mg/dL had the lowest risk of having a heart attack or dying. Both lower and higher levels (especially over 80) were associated with increased risk.
Many people were undoubtedly surprised to hear that high HDL-C was not beneficial, let alone possibly risky. After all, for years we’ve been told that LDL is “bad” because it brings cholesterol into artery walls and thus increases build-up of dangerous plaque (atherosclerosis), while HDL is “good” because it removes cholesterol from plaque in artery walls and carries it to the liver (this is called reverse cholesterol transport).
But, in fact, the Emory findings are not very surprising. Though details of the study have not been released, one key factor was that nearly all of the participants already had cardiovascular disease or were at high risk for it. It is now thought that HDL can become dysfunctional in people with certain disorders or under some other conditions, so that it doesn’t protect against heart disease and may even promote it.
Is it time to stop patting yourself on your back for having a high HDL-C number—or to stop trying to raise your low HDL-C by, for instance, exercising more, losing weight, or drinking a daily glass of wine?
Boost HDL? Maybe not
Researchers have focused on HDL-C for good reason: Many observational studies have found that people with low HDL-C (usually defined as below 40 mg/dL for men and below 50 for women) are at increased cardiovascular risk. But just because there’s an association between low HDL-C and cardiovascular disease, that doesn’t mean that low HDL-C causes it—or that raising HDL-C will help prevent it. Low HDL-C tends to go along with other metabolic abnormalities that could directly increase risk for coronary disease, such as high levels of LDL (especially the small LDL particles that are most dangerous) and increased triglycerides (fats in the blood), as well as poor health in general. Thus, the question has long been, is low HDL-C a cause of cardiovascular disease or merely a marker for it?
Genetic factors help determine the levels and characteristics of HDL components, often very strongly. For that reason, researchers have analyzed data from people with genetic variants that raise HDL-C but do not affect LDL-C, triglycerides, or related blood lipids, using a type of genetic analysis called Mendelian randomization, which allowed them to determine whether high HDL-C, in and of itself, reduces coronary risk. They found that it does not.
Moreover, within the past decade several high-profile HDL-C-boosting drugs were scrapped after clinical trials showed that they failed to produce the expected benefits, despite dramatic increases in HDL-C; one drug actually increased cardiovascular risk.
HDL and Cardiovascular Risk: A U-Shaped Curve?
Several studies have found an association between both low and high HDL-C levels and increased cardiovascular disease and death rates—that is, a U-shaped risk curve, with the lowest risk in the middle range.
Not a simple number
The relationship between HDL and cardiovascular disease is complicated, largely because HDL is so complex in structure and function—even more so than LDL. HDL is actually a family of particles in the blood that vary in size, number, density, cholesterol content, function, protein components, and other characteristics.
When people hear the terms HDL and LDL, they think cholesterol, largely because standard blood tests measure only the total amount of cholesterol these packages carry—HDL-C and LDL-C. But HDL-C (like LDL-C) tells you nothing about the characteristics of the particles themselves, such as their size and number and their ability to promote reverse cholesterol transport.
Though research has been inconsistent, it’s now thought that some forms of small, dense HDL particles are protective, while high levels of very large, less-dense HDL particles are associated with increased cardiovascular risk. (This contrasts with LDL, for which small, dense particles are most dangerous, while large, fluffy particles are believed to be relatively benign.) In addition, HDL’s effects depend on its interaction with LDL and other lipids in the blood. HDL’s potentially cardioprotective effects also depend on its roles in anti-inflammatory, anti-oxidative, anticlotting, and other biochemical processes.
So how can “good” cholesterol become “bad”? A review paper in Drugs in Context in 2018 proposed potential mechanisms. The body’s response to disorders with an inflammatory component—such as atherosclerosis, diabetes, kidney disease, or infection—could lead to alterations of protein components of HDL, so that it changes from being anti-inflammatory to pro-inflammatory, from antioxidative to pro-oxidative. Such conditions could also result in impairment of HDL’s ability to remove cholesterol from artery walls. The functionality of HDL may be affected by genetic and lifestyle factors, both of which are the focus of ongoing research.
What to do about HDL
There are many unanswered questions about HDL. It is becoming increasingly clear that there is far more to it than a single number from a basic blood lipid test. It’s hoped that researchers will eventually find drugs or other ways to maintain or improve the functionality of HDL so that it continues to stay “good.”
As for HDL-C, a low reading (below 40 mg/dL for men and below 50 for women) is still, at the very least, a marker for increased cardiovascular risk and should be considered in the context of your other risk factors, such as diabetes, obesity, or a family history of premature coronary heart disease or stroke. The same may be true of very high HDL-C, depending on your age, health, and cardiovascular risk factors.
There are several relatively new ways to measure various HDL and LDL particles, but the tests have not yet been standardized, and they are not routinely used for people at average risk. So far, the evidence about the benefits and risks of LDL particle size and density is clearer than that about HDL particles. On the horizon are other analyses that could focus on subtypes or properties of HDL particles that are relevant to cardiovascular risk and are potentially important targets for treatment.
A low or very high HDL-C number may lead your doctor to order advanced blood tests for additional lipid-related components such as HDL and LDL particle number and size, lipoprotein(a), and apolipoprotein A1, as well as markers for inflammation (such as C-reactive protein), to get a more complete picture of what’s going on.
Low HDL-C should encourage you to take the steps that improve blood cholesterol, triglycerides, and heart health in general—notably to exercise, quit smoking, eat more healthfully, and lose excess weight. Of note, research suggests that a heart-healthy Mediterranean diet modestly improves HDL’s cholesterol-removing, anti-inflammatory, and anti-oxidative capacity, though it may not increase HDL-C levels significantly. In addition, if your HDL-C is low, that may be a reason for you and your doctor to more aggressively lower your LDL-C with drugs.
This article first appeared in the UC Berkeley Wellness Letter.
Published June 05, 2019