Clinical and epidemiological studies during the last 7 decades indicated that elevated low-density lipoprotein cholesterol (LDL-C) levels and reduced high-density lipoprotein cholesterol (HDL-C) levels correlate with the pathogenesis and progression of atherosclerotic lesions in the arterial wall. This observation led to the development of LDL-C-lowering drugs for the prevention and treatment of atherosclerosis, some with greater success than others. However, a body of recent clinical evidence shows that a substantial residual cardiovascular risk exists even at very low levels of LDL-C, suggesting that new therapeutic modalities are still needed for reduction of atherosclerosis morbidity and mortality. Unfortunately, HDL-C-raising drugs developed toward this goal had disappointing results thus far. Here, we critically review the literature presenting available evidence and challenges that need to be met and discuss possible new avenues for the development of novel lipid pharmacotherapeutics to reduce the burden of atherosclerosis.
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