Is Very High HDL Good for You?  

• Epidemiologic, pathologic, and experimental studies have demonstrated a role for HDL in protection from CAD (coronary artery disease).¹  HDL has been demonstrated to reduce the risk from atherosclerosis and CVD (cardiovascular disease) by multiple pathophysiological mechanisms.² 

• Whether high HDL-C level (greater than 60 mg/dL) can be regarded as protective in all people has recently been debated. Ansell et al ³ showed that patients with CAD and HDL-C greater than 85 mg/dL carry dysfunctional HDL. High concentrations of dysfunctional HDL may be more dangerous for cardiovascular health than having low levels of functional HDL.⁴

• Although epidemiological studies and early trials suggest that increasing HDL-C by 1 mg/dL will lead to a 3% decrease in CVD events, recent data suggest that this relationship does not hold true for very high HDL-C levels, particularly when a preponderance of large HDL particles is observed. More recent data suggests that very high HDL levels might be deleterious.  No such harm is observed among people with very high levels of Apo A1.⁵ 

• Genetics data also indicate a more complex relation between HDL-C and CVD than the inverse relation found in epidemiological studies. It has long been observed that not all genetic disorders that lead to low HDL-C levels are associated with increased CVD risk, and that HDL-C is not consistently associated with CAD, implying that different pathways affecting HDL-C level may have different effects on the pathogenicity of CAD.

• Mutations affecting the function of an enzyme rarely are linked to improved metabolism or health. Polymorphisms of both the CETP gene, leading to high HDL-C levels through reduced cholesterol exchange, and the hepatic lipase gene, leading to high HDL-C levels through impaired lipolysis, have been linked to increased CVD risk.^{6, 7}  Indeed, a dysfunctional HDL is more likely associated with high, rather than low, HDL-C levels because it may often reflect altered recycling of the mature plasma HDL.

• Because of the inverse relationship between HDL-C levels and CAD risk, interventions on HDL are deemed necessary for subjects with low HDL-C concentrations. This pillar of knowledge has strong credibility because even a fully functional HDL will not achieve its biologic effects when produced at low rates and if it does not reach significant concentrations in the artery wall.

• On the contrary, high HDL-C levels are seen as protective against CAD and often used to lower risk prediction in subjects with multiple risk factors. It is essential to keep in mind that the Framingham database includes very few subjects with HDL greater than 75 mg/dL. Therefore, attribution of risk reduction for HDL above this mark is based on a dangerous extrapolation of data and does not take into consideration the possibilities that mutations in HDL-regulating genes may be responsible for the phenotype or that HDL is accumulating in plasma because of inability to unload cholesterol and oxidized lipids.⁸

• A recent analysis of a statin trial (IDEAL) and of an observational study (European Prospective Investigation of Cancer-Norfolk) determined that the classic inverse correlation between HDL-C and CHD risk is not sustained when evaluating subjects with HDL greater than 70 mg/dL, who appear to present increased risk even when on statin therapy.⁵ CVD risk was also increased by the presence of large HDL particles, suggesting that dysfunctional reverse cholesterol transport with accumulation of lipid-loaded HDL in plasma and high HDL-C levels is a proatherogenic condition.

• In this light, the relationship between HDL and arterial disease should be revisited to clarify that the protection obtained from physiologic HDL-C elevations induced by lifestyle maneuvers or currently available drugs does not necessarily extend into the high range (>75 mg/dL), where a dysfunctional HDL may instead become an aggravating factor in the progress of atherosclerotic disease.⁴

• A dysfunctional HDL may be a cause or cofactor in the development of diabetes. In support of this concept, investigators of the FINNS Study have recently reported on a genetic association between diabetes and high HDL in subjects who are leaner and have a healthier CVD risk profile than diabetics without the high HDL trait.⁹ Although this was interpreted as another piece of evidence that high HDL-C concentrations can negatively predict CV rates, a tantalizing possibility is that a dysfunctional HDL is responsible for diabetes development in subjects without insulin resistance.

• All of this negative potential for high HDL-C concentrations should be considered in clinical practice while keeping in mind that HDL-C can also increase to greater than 75 mg/dL for reasons that are compatible with the classical concept of increased vascular protection, such as strenuous aerobic exercise and use of therapeutic doses of niacin. 

Sources

1. Natarajan P, Ray KK, Cannon CP. High-density lipoprotein and coronary heart disease: current and future therapies. J Am Coll Cardiol. Mar 30 2010;55(13):1283-1299.

2. Ragbir S, Farmer JA. Dysfunctional high-density lipoprotein and atherosclerosis. Curr Atheroscler Rep. Sep 2010;12(5):343-348.

3. Ansell BJ, Navab M, Hama S, et al. Inflammatory/antiinflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment. Circulation. Dec 2 2003;108(22):2751-2756.

4. Fazio S, MF L. HDL therapeutics and cardiovascular prevention. J Clin. lipodology. 2010;4:411-419.

5. van der Steeg W A, Holme I, Boekholdt SM, et al. High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies. J Am Coll Cardiol. Feb 12 2008;51(6):634-642.

6. Fazio S, Linton MF. Elevated high-density lipoprotein (HDL) levels due to hepatic lipase mutations do not reduce cardiovascular disease risk: another strike against the HDL dogma. J Clin Endocrinol Metab. Apr 2009;94(4):1081-1083.

7. Borggreve SE, Hillege HL, Wolffenbuttel BH, et al. An increased coronary risk is paradoxically associated with common cholesteryl ester transfer protein gene variations that relate to higher high-density lipoprotein cholesterol: a population-based study. J Clin Endocrinol Metab. Sep 2006;91(9):3382-3388.

8. Feldman DS, Novack DH, Gracely E. Effects of managed care on physician-patient relationships, quality of care, and the ethical practice of medicine: a physician survey. Arch Intern Med. 1998;158(15):1626-1632.

9. Shtir C, Nagakawa IS, Duren WL, et al. Subsets of Finns with high HDL to total cholesterol ratio show evidence for linkage to type 2 diabetes on chromosome 6q. Hum Hered. 2007;63(1):17-25.