It may go against decades old wisdom, but high density lipoprotein- cholesterol (HDL-C) may not be “good” cholesterol every patient now thinks it is. Every physician has at one point or another discussed “good cholesterol” and “bad cholesterol,” the colloquial terms for HDL and LDL respectively, with her patients. The purported benefit of HDL derived from its function as a reverse cholesterol transporter, and with its associated anti-inflammatory and antithrombotic properties.1 While older research seemed to show a link between higher HDL-C and fewer cardiovascular disease (CVD) events2, newer data is failing to reproduce this association. Increasingly, HDL-C appears to simply be a cofounding factor; a marker that happens to be elevated in healthy people who exercise, eat well and don’t smoke, but in and of itself, does not affect cardiovascular risk.3,4
The difference between HDL-P and HDL-C is important
HDL is measured by determining the cholesterol content of HDL, denoted HDL-C. An alternative method of evaluating HDL is by “counting” the number of HDL particles present in the plasma (HDL-P). HDL-P encompasses the range of HDL particles from the larger, cholesterol-rich particles to the smaller, more lipid poor variants. This is vital because new research suggests that HDL-C drastically underestimates the variety of HDL in the plasma and can give a one-sided view of the cholesterol profile.1 This difference can be captured, it seems, by measuring HDL-P.
The Veterans Affairs High Density Lipoprotein Trial showed that gemfibrozil improved HDL-C, reduced the risk of coronary artery disease, and furthered the case for the benefits of HDL-C. However, reanalysis of the findings revealed that while gemfibrozil increased HDL-C, it more significantly increased total HDL-P by increasing the number of small cholesterol poor HDL-P. In the study LDL-P and HDL-P had significant associations with CHD events, whereas LDL-C and HDL-C did not.2
Since then, two other major studies, looking at niacin and cholesteryl ester transfer protein (CETP) inhibitors have failed to show a connection between increasing HDL-C and improving cardiac outcomes, furthering the consensus that HDL-C, at most, serves as a marker for good health, but is not an effective target for improving it.3 Furthermore, research indicates that individuals with very high levels of HDL-C (greater than 70 mg/dL in men and greater than 90 mg/dL in women) tend to have higher rates of non-cardiovascular and all-cause mortality, perhaps indicating that they have an overabundance of dysfunctional HDL.5
All of this research indicates that HDL is a complex particle. It comprises multiple components of cholesterol and proteins in different sizes, shapes and charges. Even its major protein, apolipoprotein AI (apoAI), may exist in 1 to 5 copies per HDL particle.1 In addition, HDL is assembled in the plasma and continues to evolve while being transported in the plasma. It is therefore plausible that different HDL particles have different effects on CVD and cerebrovascular disease and cannot be easily categorized into a single homogenous group. It becomes necessary, then, to look more at HDL function, rather than its cholesterol content to determine its true significance.
HDL function rather that HDL quantity
HDL function, rather than cholesterol content, appears to be a more useful diagnostic tool. A direct measurement of HDL function is cholesterol efflux capacity (CEC), which is the ability of serum depleted LDL and apolipoprotein B (apoB) containing lipoproteins to remove cholesterol from macrophages.6 However, commonly encountered medical comorbidities such as diabetes, acute coronary syndrome, systemic inflammation and even menopause affect HDL functionality, changing HDL from a cardioprotective particle to one that promotes inflammation and oxidization of LDL. Studies show that traditional HDL-C affects only 33% of the variance in cholesterol efflux capacity, indicating it is a poor proxy of HDL function. In patients with cardiac comorbidities then, elevated HDL-C may prove to be a negative marker of health.6 In fact, in post-menopausal women, elevated HDL-C can be associated with increased risk of CVD. In contrast, HDL-P levels are not affected by menopause and continues to be inversely associated with CVD risk in both men and women.6
Many researchers suggest that we should be looking at the particles rather than cholesterol content. For example, small LDL particles contain less cholesterol, but a higher number of small dense (and artherogenic) LDL-P, despite a lower overall LDL. As such, particles appear to be better indicator of cardiovascular risk than total cholesterol level. While this is straightforward for LDL, the numerous particles associated with HDL make it difficult to know exactly which particle to target. Increased HDL-C, when beneficial, tends to be associated with increased levels of the small HDL3 subclass2,6, which are effective at removing cholesterol from macrophages and have less cholesterol per particle. However, when making clinical assessments it seems overly narrow to focus on this subclass alone.
How do we test for HDL function?
Unfortunately, tests to determine HDL function are not clinically available. The cholesterol efflux capacity is primarily a research tool and requires radioisotope labeled cholesterol and cultured macrophages, which is a complex and time consuming method (and costly).5,7 A Japanese group led by Harada et al have determined a test for HDL function that can be useful for clinical applications and takes only about 6 hours.5 The test evaluates cholesterol uptake capacity, a correlate of cholesterol efflux capacity.5 Unfortunately, the test is not yet clinically available and may not bear out upon further clinical testing.
In the meantime, we can clinically measure HDL-P. This is not a perfect solution as there are many subclasses of HDL and they are not always well differentiate by density, the current method for distinguishing different forms of HDL-P. While the majority of clinically available tests only measure HDL-P total, a more clinically useful measurements would be to quantify HDL-P into three size groups—small, medium and large—which have different clinical correlates to CVD risk. For example, in a study looking at HDL-P changes in post-menopausal women, it appeared that medium and large HDL-P correlated most with cholesterol efflux capacity, suggesting that these two were better markers of HDL function.6 These findings are not conclusive however, as CEC and HDL-P were raised in post-menopausal women, a group that is at increased risk for cardiovascular disease and should have markers suggestive of that risk.
Until we have better clinical tools to measure HDL in the context of its ability to protect against or cause cardiovascular disease, one should look focus on LDL and other cardiovascular risk factors without dwelling too much on HDL-C levels. In some cases, clinicians may want to order HDL-P testing especially if they have access to particle size information with these labs. At any rate, it is probably time to stop calling HDL “good” cholesterol both amongst ourselves and in front of patients. Lastly, pharmaceuticals at our disposal primarily decrease LDL—increasing HDL with these drugs was always by-and-large a happy side benefit. Thus, it is probably better to have patients focus on the LDL number. If they are interested in HDL, encourage them to do the things that naturally improve cardiovascular health (e.g., smoking cessation, exercise, proper diet, etc.) and HDL—both good and bad parts—will move closer to where they need to be.
1. Davidson WS. Hdl-C Vs Hdl-P: How Changing One Letter Could Make a Difference in Understanding the Role of High-Density Lipoprotein in Disease. Clinical Chemistry. 2014;60(11):e1-e3. doi:10.1373/clinchem.2014.232769
2. Otvos JD, Collins D, Freedman DS, et al. Low-Density Lipoprotein and High-Density Lipoprotein Particle Subclasses Predict Coronary Events and Are Favorably Changed by Gemfibrozil Therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation. 2006;113(12):1556-1563. doi:10.1161/CIRCULATIONAHA.105.565135
3. Lloyd-Jones DM. Niacin and Hdl Cholesterol–Time to Face Facts. N Engl J Med. 2014;371(3):271-273. doi:10.1056/NEJMe1406410
4. Toth PP, Barter PJ, Rosenson RS, et al. High-Density Lipoproteins: A Consensus Statement from the National Lipid Association. J Clin Lipidol. 2013;7(5):484-525. doi:10.1016/j.jacl.2013.08.001
5. Harada A, Toh R, Murakami K, et al. Cholesterol Uptake Capacity: A New Measure of Hdl Functionality for Coronary Risk Assessment. The Journal of Applied Laboratory Medicine: An AACC Publication. 2017. doi:10.1373/jalm.2016.022913
6. El Khoudary SR, Hutchins PM, Matthews KA, et al. Cholesterol Efflux Capacity and Subclasses of Hdl Particles in Healthy Women Transitioning through Menopause. J Clin Endocrinol Metab. 2016;101(9):3419-3428. doi:10.1210/jc.2016-2144
7. Hutchins PM, Ronsein GE, Monette JS, et al. Accurate Quantification of High Density Lipoprotein Particle Concentration by Calibrated Ion Mobility Analysis. Clinical chemistry. 2014;60(11):1393-1401. doi:10.1373/clinchem.2014.228114