If the data for high-density lipoprotein (HDL) were more clearly divergent, we could call it a paradox. But, in fact, it is not a paradox. The data are more confusing and complex than that—it is in fact more of an enigma. Indeed, the HDL enigma not only persists—it appears to be expanding.
For those interested in cardiovascular risk reduction, the prospect of raising HDL to the same extent as we now lower low-density lipoprotein (LDL) has been tantalizing. The epidemiological evidence suggested a steeper curve between HDL and risk of future cardiovascular events than that seen for LDL. Indeed, some reports associated hyperalphalipoproteinemia—markedly elevated levels of HDL—with not just decreased cardiovascular risk but perhaps even longevity. Small trials supported this prospect, with the suggestion of decreased atherosclerosis if not actual cardiac events when efforts were made to raise HDL. However, there were cracks in the veneer that also suggested limitations in our understanding of the science and clinical therapeutics.
In some populations, certain genetic HDL variants that seemed to protect against atherosclerosis, such as apolipoprotein A1_Milano, were not associated with increased HDL levels. Various approaches to raising HDL did not return the positive results that were expected in large prospective clinical trials: one trial with fibrate therapy was positive in the absence of statin therapy, and two other trials were negative in settings in which statin therapy was used, either disproportionately in the placebo group through drop-in therapy (Fenofibrate Intervention and Event Lowering in Diabetes, FIELD) or as part of the protocol (Action to Control Cardiovascular Risk in Diabetes, ACCORD-Lipid).
In the first large-scale trial with a cholesteryl ester transfer protein (CETP) inhibitor (Investigation of Lipid Level management to Understand its iMpact IN ATherosclerotic Events, ILLUMINATE), HDL was dramatically raised but events increased instead of decreasing, perhaps as a result of off-target effects. Other CETP inhibitors continue to be pursued. Most recently, the Adjuvant Interferon in Melanoma-High Risk (AIM-HIGH) trial (released when this monograph was already completed), testing the effects of statin plus niacin, reported no difference than with statin alone. With all these studies, multiple issues and factors may have contributed to the results seen. It would seem the complexity of HDL biology is matched only by the complexity of therapeutic efforts to favorably modulate it.
Perhaps the best, if not only, tool available to both the clinician and scientist in dealing with an enigma is further study. In this regard, the chapters in this monograph are contributed by two of the foremost authorities in the area of HDL and therapeutics. Ernst Schaefer has provided fundamental insights into the nature of HDL and is an internationally recognized authority on HDL and lipoprotein metabolism in general. Here he and his colleagues closely examine the nature of HDL deficiency states and their relationship with premature coronary artery disease. Michael Davidson is also a well-known and well-respected lipid specialist with an unparalleled breadth of experience in lipid-modulating therapeutics. Davidson reports on the most relevant issue in the post-statin era: how to approach the patient with combined dyslipidemia.
Enigmas can be overcome. If we ever are to optimize the use of HDL as an indicator of cardiovascular risk or its utility as a therapeutic target, it will require greater understanding into HDL biology, the clinical impact of treating it, and how those therapeutic approaches may differ. This mission also demands that we recognize and remember what we have already learned through prior study. This monograph is an invaluable resource in pursuit of these objectives.