Vol 3, No 2 (2024)

The relationship between plasma cholesterol levels and the risk of cardiovascular events is well known. When analysing plasma cholesterol levels and integrating data from several studies, including the Pooling Project, the Framingham Heart Study and the Israeli Perspective Study, a consistent association was confirmed worldwide. This pattern was particularly evident in the Seven Countries Study.1 The observed variations in risk across different populations are largely due to the baseline risk values of these populations. For example, the Framingham Heart Study has shown that its results are applicable in any country by adjusting for baseline risk, suggesting a universal pattern in the relationship between cholesterol levels and cardiovascular risk. This has led to debate because the relationship has been oversimplified and presented as linear when it is not necessarily so. For example, an increase in total cholesterol of 0.5 mmol/L (about 20 mg/dL) correlates with a 12% change in mortality risk. In agreement with this observation, data from the Cholesterol Treatment Trialists' (CTT) Collaboration have shown that lowering low-density lipoprotein cholesterol (LDL-C) by 1 mmol/L reduces the risk of coronary heart disease by 22-23% reduction, which is consistent with data from clinical trials.

The focus of this review are the novel and future approaches to reduce the cardiovascular (CV) residual risk by reducing the apoB-containing lipoproteins levels. We assume that in the clinical practice a combination therapy based on the use of high intensity statins, ezetimibe, bempedoic acid, mAbs anti PCSK9 or Inclisiran may reduce most of the cardiovascular risk associated with the apoB containing lipoproteins and may contribute to achieve the LDL-Cholesterol (LDL-C) goal in the majority of individuals at high and very high risk. However we can assume that a proportion of well treated patients will develop new cardiovascular events. Many factors such as the genetic background, the pre-existing burden of disease and the residual risk attributable to triglycerides, inflammation, coagulation and platelets may explain this recurrence of events. We discuss some novel options to reduce the residual risk due to the two main apoB-containing lipoproteins, LDL-C and Lp(a), that are:
-the newest-generation CETP inhibitor, Obicetrapib; the oral PCSK9 inhibition; the novel approaches to reduce Lp(a) plasma levels (antisense oligonucleotides-ASO; rna interfering-Sirna; assembly inhibition-; the PCSK9 gene editing.