The 2 Faces of High HDL


Recently, my former college classmate and long-standing colleague, Dr. Annabelle Rodriguez, published an intriguing review on the paradox of high HDL that details her elegant work.  She found specific genetic variants associated with high HDL (equal to or greater than 60 mg/dL) to be linked to increased (rather than decreased) risk of heart disease.

These insights fall flatly on the face of earlier studies.  That is, between the 1970s into the late 90’s, we were taught that high levels of HDL (“the  good cholesterol”) protect the heart.  The body of work that originated in the U.S. was largely conducted in Framingham, MA where an inverse association between HDL cholesterol and risk of heart disease was uncovered.  With respect to high levels of HDL, each 5 mg/dL increment above the median (45 mg/dL for men and 55 mg/dL for women), corresponded to a 10-15% lower risk of heart disease.  Other studies not only found high HDL to be inherited but also associated with longevity as reported by the Cincinnati group led by Dr. Charles Glueck, my mentor during medical residency.

Because high levels of HDL cholesterol were seemingly protective to the heart, studies were then designed to determine the extent to which raising HDL might reduce the risk of future cardiovascular events.  Unfortunately, the two potent HDL compounds tested, niacin and cholesteryl ester transfer protein (CETP) inhibitors both failed. In other words, raising HDL cholesterol with these agents did not translate into reduced cardiovascular risk.  Around this time, other observational studies found very high HDL (~80 mg/dL and higher) to be associated with increased cardiovascular risk, as elaborated upon by Dr. Rodriguez…hence “the HDL paradox”.

So how might we resolve this discrepancy?  First, let me provide full disclosure as we have done considerable work in this area. For one, not all genetic cases of high HDL correlate with increased risk of heart disease.  Notwithstanding the genetic variants described by Dr. Rodriguez found to be associated with elevated risk (e.g., SCARB1, LAG3),  we and others have recently identified families with extremely high HDL (greater than 100 mg/dL) to be at low cardiovascular risk.  And even though CETP inhibitors do not effectively reduce risk, there are individuals with CETP deficiency who appear to be protected as we’ve  reported.

With respect to recent observational studies suggesting that high HDL may be problematic rather than protective, I have 2 comments.  First, one should interpret these data very cautiously because they do not adequately account or adjust for “confounders” such as excessive alcohol intake and chronic hormone/steroid use, both of which may significantly raise HDL cholesterol levels.  Unfortunately, alcohol intake, especially when excessively used, is notoriously underreported in clinical practice as well as in observational studies.

Secondly, after revisiting the Framingham Study, we found that high HDL was indeed cardioprotective.  This was provided that levels of other risk factors including lipoproteins/lipids such as LDL (“the bad cholesterol”) and triglycerides were normal.

Bottom Line: There are 2 faces of high HDL. If you have high HDL (60 mg/dL and greater) with a family history of longevity OR If your HDL cholesterol levels are higher than 60 mg/dL AND you don’t smoke, are physically active, do not have a history of hypertension or diabetes, do not take steroids/hormones (that artificially raise HDL) and do not excessively consume alcohol (no more than 1 ounce on an average day), put on a HAPPY face as your heart is likely to be protected.  For all others with high HDL, a more subdued face may be in order until risk factors for heart disease are under more optimal control.  

Dr. Michael Miller is Professor of Cardiovascular Medicine at the University of Maryland School of Medicine in Baltimore, Maryland.



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