Nearly every consumer story on high-density lipoprotein cholesterol (HDL-C) will include the phrase "good cholesterol." Yet HDL-C–raising drugs, including niacin[1] and cholesterylester transfer protein inhibitors,[2] failed to show a benefit in cardiovascular disease outcomes and multiple population studies show a U-shaped curve indicating a higher risk for all-cause mortality in people with very high levels.

Is it time to retire the phrase "good cholesterol"? "Absolutely," responded Robert Rosenson, MD, Mount Sinai Icahn School of Medicine, New York City, who has chaired four international working groups on the biology of the misunderstood particle. "HDL can be a good, bad, or neutral particle," he said, explaining by phone that it is the surface proteins that confer the cardioprotective effects. Loading up HDL particles with cholesterol in a bid to lower cardiovascular risk was a mistaken therapeutic strategy, he added.

Early Clues

Ironically, one of the early trials of a HDL-C–raising drug suggested as much. The Veterans Affairs High-Density Lipoprotein Intervention Trial showed a reduction in coronary artery disease events when gemfibrozil was given to men with low baseline HDL-C levels.[3] Back in 2006, a case-control substudy using nuclear magnetic resonance (NMR) spectroscopy revealed that the modest increase in HDL-C masked a higher increase in total HDL particles, particularly the small HDL particles that are relatively cholesterol-poor.[4] The authors speculated that "higher numbers of HDL particles might promote greater cholesterol efflux and protection of LDL [low-density lipoprotein] from oxidative changes." This theory was met with doubt by editorialists.[5]

Recent data from two population-based cohorts in Copenhagen of over 100,000 people showed that all-cause mortality rates increased significantly for men with HDL-C levels above 97 mg/dL and for women above 135 mg/dL.[6] This mirrored findings from a Canadian big data cohort of more than 630,000 individuals that saw higher risk for noncardiovascular death at fasting levels above 70 mg/dL for men and 90 mg/dL for women.[7] The researchers hypothesized that extremely high levels may reflect dysfunctional HDL-C.

Rosenson cautions against focusing on HDL-C levels at all. "It is the number of HDL particles and not the cholesterol content that is important," he said. By phone, Matthew Budoff, MD, Los Angeles Biomedical Research Institute, agreed that total HDL particles are a better measure of the antiatherogenic features. He doesn't believe that very high HDL-C levels are necessarily bad, using the analogy of a barrel that is filled with ping-pong balls or basketballs to represent volume of HDL-C. "Some people will have very high levels of HDL-C and a lot of particles, so they're protected, but others will have high HDL-C and very few particles." Dysfunction appears to be independent of the HDL-C level.[8]

Budoff isn't ready to give up on the terms "good cholesterol" and "bad cholesterol"; he finds that they help patients realize that total cholesterol alone is not a good metric. "For 95% of people, it [HDL-C] is good," he said.

The "Good"

The inverse association of HDL-C with coronary artery disease[9] sparked research on agents to boost low levels, typically defined as < 40 mg/dL in men or < 50 mg/dL in women. However, Rosenson sees HDL-C as little more than a marker of lifestyle: Levels tend to be higher in people who exercise more, weigh less, and don't smoke.

HDL got its good name primarily because of its role in reverse cholesterol transport as the body's Roomba®, vacuuming up cholesterol from macrophages. In addition, HDL has anti-inflammatory[10] and antithrombotic[11] properties, and may ameliorate endothelial dysfunction.[12]

This has led to calls to focus on measuring HDL function, not HDL-C.[13] Assays that measure HDL efflux capacity have been shown to better predict cardiovascular events than HDL-C level.[14] However, such tests are not clinically available, and there are no international standards for them or others that aim to measure various aspects of HDL function.

What triggers dysfunctional HDL? It has long been known that such conditions as acute coronary syndrome,[15] diabetes, or systemic inflammation can alter HDL from a cardioprotective particle to one that promotes inflammation and LDL oxidation.[16] Budoff and fellow investigators for the MESA study suggest that the transition to menopause should be added to that list. In the main MESA cohort, HDL-C was inversely associated with CAD and carotid intima-media thickness (cIMT).[17] In contrast, in almost 1500 postmenopausal women, HDL-C was positively associated with increased cIMT.[18] NMR analysis suggested that small HDL particles are less susceptible to adverse modification at menopause than larger particles. HDL particles were inversely associated with cIMT for men and women—a relationship that held even after adjustment for atherogenic particles.

What to Measure?

If tests for HDL function are not ready for prime time, could measuring the size of the subfractions be the way to go, because very small cholesterol-depleted HDL particles are the main players in cholesterol efflux?[19] This, too, is overly simplistic for Rosenson, who cautioned that there are many subclasses of HDL and they're not just differentiated by density. There are more than 60 different proteins associated with HDL, but most particles will only carry a few. Which proteins confer which properties is not fully understood either. The flaw with HDL-C–raising therapies, he noted, is that loading up the particle with cholesterol led to the loss of some surface proteins important in cardioprotection.

Both Budoff and Rosenson like non–HDL-C because it captures all atherogenic particles. But what about patients with very high levels of potentially dysfunctional HDL-C? Budoff explained that when he has a patient of uncertain risk with high LDL-C and very high HDL-C, he will get the HDL particle number; such tests are commercially available. He might also suggest she (he can't remember seeing a man with HDL-C > 100 mg/dL) get a calcium score. "If the coronaries are clean, the HDL is working," he said.

The HDL hypothesis, on the other hand, is not. As a recent editorial put it: "There remains a high degree of ignorance regarding the role of HDLs as either protectors or causes of disease."[13] Rosenson for one would like to hit the reset button and begin anew by focusing on the particle rather than the so-called "good" cholesterol.

Drs Rosenson and Budoff reported no relevant financial relationships.

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