PCSK9i
PCSK9 is expressed primarily in the liver and small intestine and plays a very important role in cholesterol metabolism (44). PCSK9 is secreted by liver cells, circulates in plasma, binds to LDLr, and is subsequently internalized together with the LDLr, thereby promoting the cellular degradation of the receptor. This reduction in the amount of LDLr at the surface of hepatocytes is responsible for the increase of LDL-C concentration in plasma. PCSK9 and LDLr binding may be interrupted by different mechanisms (45). The use of human monoclonal antibodies against PCSK9 has proven to be effective as monotherapy leading to a 57% reduction in LDL-C, a 46% reduction in ApoB, and a 24% reduction in Lp(a) (46).
The FOURIER was a trial performed with evolocumab (PCSK9i) that showed cardiovascular benefit (22) with RRR of 50% in patients with ASCVD and elevated LDL-C levels treated with moderate or high intensity statins. The addition of evolocumab showed unprecedented LDL-C average levels of 30 mg/dL and 42% of patients reached LDL-C levels < 25 mg/dL (47).
The ODYSSEY OUTCOMES study (48) evaluated the effect of alirocumab (PCSK9i) on residual risk reduction in patients with a recent acute coronary syndrome. The results further demonstrated the utility of PCSK9i in significantly reducing major cardiovascular events and safely reaching very low LDL-C levels.
Most guidelines recommend goals for LDL-C reduction that have been clinically useful as a measure of therapeutic success. In clinical practice, however, not all patients achieve their LDL-C goal with statins alone and increasing awareness of this treatment gap has led to the need to consider the routine use of combination lipid lowering therapy (LLT) (Table 2).
Table 2. Intensity of lipid lowering treatment.