For decades, doctors have advocated raising high-density lipoprotein (HDL) cholesterol for reducing heart disease risk. Since a low level of HDL is correlated with an increased risk for heart attack and stroke, achieving a high level has long been considered a goal. But that guidance could be changing.
In recent years, research has painted a very different picture of HDL. Not only does it play less of a role in promoting heart health than was once believed, but evidence suggests that very high levels might actually contribute to increased cardiovascular disease (CVD) risk, and lead to worse outcomes in those who already have CVD.
Is it time to stop trying to boost low HDL with practices like weight loss, exercise, and medication?
The HDL backstory
To take a step back and offer some context on the subject, lipoproteins are packages of lipids (fats) and proteins that are transported through the bloodstream. Low-density lipoprotein (LDL) has earned its reputation as the “bad” cholesterol because when its levels are high, it deposits cholesterol in arteries, leading to plaque buildup. Rupture of plaque could trigger a blood clot that blocks blood flow and delivery of oxygen to the heart (leading to a heart attack) or brain (leading to a stroke).
HDL has long been considered the “good” cholesterol because some HDL particles pick up excess cholesterol from blood vessel walls and deliver it to the liver (called reverse cholesterol transport), which then breaks it down and removes it from the body.
From “good” to questionable
Early observational studies contributed to the positive thinking about HDL. In 1977, the groundbreaking Framingham Heart Study showed that people with an HDL cholesterol level above 65 milligrams per deciliter (mg/dL) were eight times less likely to have cardiovascular disease (CVD) over a four-year follow-up than people whose HDL was below 35 mg/dL. A group of four studies released in the late 1980s found that for every 1 mg/dL increase in HDL, CVD risk dropped by 2 to 3 percent.
Over the past decade, as researchers have delved further into the connection between HDL and CVD, they’ve discovered that the relationship is more complex and not quite as positive as was first thought. Collectively, studies have shown that while low HDL (below 40 in men and 50 in women) is associated with increased CVD risk, so is excessively high HDL. An HDL level over 80 has been associated with a higher risk for CVD, dying from CVD, and dying from any cause.
A 2022 study in JAMA Cardiology looked at around 20,000 people with coronary artery disease. The authors found that those with HDL levels above 80 had a 71 percent greater risk of dying from CVD, and an even higher risk of dying from all causes, than those with HDL levels between 40 and 60.
High HDL cholesterol has also been linked to increased risk for osteoporosis. In another study in JAMA Cardiology, in 2023, people with the highest HDL levels had a 33 percent greater risk for fractures than those with the lowest HDL levels, even after accounting for typical fracture risks like age, gender, and exercise. Although the reasons are unclear, some research suggests that HDL reduces bone mineral density through mechanisms that lower the number of osteoblasts—cells that help form new bone.
A complicated relationship
While there is a relationship between low HDL cholesterol and CVD, it’s a complicated one. Having low HDL doesn’t necessarily cause CVD, and raising HDL won’t necessarily help prevent it.
For example, several CETP (cholesterol ester transfer protein) inhibitor drugs—which dramatically increase HDL levels—weren’t pursued further after clinical trials showed that they failed to protect against CVD.
Adding to the complication, HDL isn’t a single particle—it’s a whole family of particles that vary in their composition, size, and ability to clear cholesterol from blood vessels. Small and dense HDL particles seem to be most effective at removing cholesterol from arteries, while large, less-dense HDL particles can lose this protective function. (The opposite is true for small, dense LDL particles, which are particularly harmful and contribute to artery plaques.)
When “good” cholesterol turns “bad”
Along with carrying cholesterol from your blood vessels, HDL can also lower inflammation, prevent blood clots, and protect your cells and tissues against the harmful effects of oxidation. But in some cases, such as when you have body-wide inflammation from a condition like atherosclerosis, diabetes, or an infection, HDL can change in ways that make it pro-inflammatory and pro-oxidative. Inflammatory conditions might also impair HDL’s ability to clear cholesterol from artery walls.
Both genetic and lifestyle factors are also thought to affect HDL’s function. Currently, researchers are studying the mechanisms behind HDL’s functions and investigating medications and other methods to enhance its positive attributes.
BOTTOM LINE: The “sweet spot” where HDL offers more benefits than risks appears to be in the range of 40 to 80 mg/dL. Many factors, from genes to excess alcohol use, can raise HDL cholesterol to unhealthy levels.
Until scientists know more about HDL and its role in cardiovascular risk, you should focus more on your LDL level because its relationship with heart health is clearer. If you have high LDL, your doctor will likely recommend that you take steps to improve your heart health by eating a diet that emphasizes vegetables, fruits, and whole grains; exercising more; losing weight if you’re overweight; not smoking; and if your LDL level remains high, taking a statin or other cholesterol-lowering drug.
