Key result
CETP-inhibition therapies failed to improve atherosclerotic vascular disease secondary prevention despite increasing HDL-C, shifting research focus toward improving HDL complex functionality.
The focus of HDL research must shift from increasing HDL-C concentration to improving HDL functionality, as high HDL-C does not universally protect against all cardiovascular diseases such as aortic stenosis.
HDL complex has multiple functions. There is some parallelism between the plasma HDL-cholesterol (HDL-C) concentrations and the HDL complex atheroprotective function, but those values only measure the reverse C-transport. Multiple epidemiological studies have shown that a high HDL-C level is a strong marker of protection against atherosclerotic vascular disease (AVD) development, but in about 10% of patients, there is no correlation between AVD presence or absence and low or high HDL-C values, respectively. Plasma HDL-C concentrations have multiple genetic determinants, but most of the genetic profiles responsible for the association of high HDL-C levels with atheroprotection are not yet identified. A meta-analysis demonstrated that the HDL capacity of C-acceptance from macrophages is inversely associated with AVD prevalence but is independent of HDL-C values. CETP-inhibition therapies, in spite of up to 133% HDL-C increases, failed to improve AVD secondary prevention. As a consequence, the main focus of research has changed and resides now on attempts to improve HDL complex functionality. Elderly AVDfree aortic stenosis patients represent a natural laboratory terrain for use in studies to identify the HDL complex components responsible for successful atheroprotection. However, the reasons why HDL complex, competent for AVD protection for several decades, fails to prevent aortic sclerosis/calcification in the same patients, remain unknown.
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Álvaro D.B. Bordalo (2018) conducted a review in Atherosclerotic vascular disease and calcific aortic valve disease. HDL-C raising therapies (CETP inhibitors) was evaluated. CETP-inhibition therapies failed to improve atherosclerotic vascular disease secondary prevention despite increasing HDL-C, shifting research focus toward improving HDL complex functionality.
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