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.