PCSK9 Inhibitors: Clinical Relevance, Molecular Mechanisms, and Safety in Clinical Practice.

Coronary artery disease (CAD) is one of the leading causes of mortality. High circulating levels of low-density lipoprotein (LDL) in the blood are associated with cardiovascular mortality, whether through an etiological role or through its association with the progression of CAD per se. Randomized clinical trials have shown that, when LDL levels are reduced, cardiovascular risk is also reduced, which reinforces this association. The first major trial involving a hypolipidemic agent of the statin family, the Scandinavian Simvastatin Survival Study (4S), was published in 1994 and found a significant reduction in mortality in patients at high cardiovascular risk. However, even in subsequent studies with different statins, a residual risk persisted, and this seems not to have changed over time; it is speculated that this risk may be due to statin intolerance. In this scenario, the potential exists for novel hypolipidemic agents to drive a true revolution in the therapy of dyslipidemia. The recent discovery of PCSK9 inhibitors (PCSK9i), a class of hypolipidemic monoclonal antibodies, is extremely promising. PCSK9 inhibition is capable of promoting a mean LDL reduction of up to 60%, with potential for very significant clinical repercussions, as every 38 mg/dL reduction in LDL appears to be associated with a 22% reduction in cardiovascular risk. This review addresses a brief history of PCSK9i, major trials of these drugs, cardiovascular outcomes, and aspects related to their efficacy and safety. Finally, the molecular mechanisms and possible pleiotropic effects of PCSK9i are also discussed.