Novel strategies targeting residual risk: The promise of PCSK9 inhibition

Stroes further elaborated on achieving additional LDL-c reduction beyond statins, focussing on PCSK9 inhibitors. He further underscored the significance of LDL-c-lowering, as illustrated by the beneficial relation between genetically and therapeutically lower LDL-c and coronary heart disease (CHD) risk and between statin-achieved LDL-c levels and cardiovascular CV risk. These beneficial relationships have also been observed in individual trials such as TNT, JUPITER and PROVE-IT1,10-11.

Using statins, only 20% of hypercholesterolaemic patients achieve an LDL-c level <70 mg/dL as specified by guidelines and a similar proportion of FH patients reach their LDL-c target. Moreover, adverse effects like muscle symptoms appear to be a major cause for therapy discontinuation and thereby reduce survival changes. Therefore, additional LDL-c-lowering therapy is needed in high-risk patients, special patient populations in which the LDL-c goal is not achieved with statins, such as FH patients, or in patients with adverse effects on statins.

Like ezetimibe, PCSK9 inhibitors can further lower LDL-c levels. Under normal circumstances, PCSK9 can bind the LDL receptor (LDLR), whereupon it is degraded in the liver. PCSK9 antibodies interfere with this process, resulting in enhanced levels of LDLR proteins on the cell surface that can catch LDL particles from the circulation and thereby target LDL for degradation. It has been shown by genetic studies that loss of function of PCSK9 results in low LDL-c levels and low CHD risk. Furthermore, an additive effect of having both a PCSK9 SNP and HMGR SNP12, a protein that is involved in the LDL-c metabolism targeted by statins, is suggested. This suggests that additional PCSK9 inhibition will benefit patients at high CV risk.

CV benefit gained by PCSK9 inhibition has already been shown with the PCSK9 inhibitor evolocumab that induced a rapid LDL-c decrease of approximately 50-60%. This reduction was persistent for at least 52 weeks13-14. Furthermore, the magnitude of this PCSK9-inhibiting effect was independent of baseline characteristics15. In statin-intolerant patients, LDL-c reduction was similar, and evolocumab was well tolerated14. The safety of PCSK9 inhibitors can only be evaluated in about 5 to 10 years, but up to now there do not seem to be any major adverse effects. Moreover, efficacy data of the OSLER study showed a trend towards reduced CV disease using evolocumab14. Another PCSK9 inhibitor, alirocumab, showed similar results16.

Inflammatory instable lesions importantly contribute to the increased risk of recurrent events in the first year after ACS. It is still questionable whether PCSK9 inhibitors have similar anti-inflammatory effect similar to statins. Although CRP levels do not seem to change after PCSK9-inhibiting treatment, very preliminary data of Stroes do not rule out a protective effect of PCSK9 inhibitors through anti-inflammatory mechanisms. To further corroborate this possible protective effect, Stroes went back to the causal effects of atherosclerosis, which is dictated by macrophages. It was recently shown that next to hsCRP, accumulation of white blood cells, such as macrophages, in the atherosclerotic plaque may predict the overall inflammatory state of the aortic atherosclerotic wall. Preliminary data now seem to indicate that a reduction in LDL-c through PCSK9 inhibition or other mechanisms, decrease the increased mobility of specific white blood cells towards the plaque, which had been activated when cholesterol levels increased. These data may therefore suggest that PCSK9 inhibitors, or any other mechanism that reduces LDL-c, might affect inflammation through alleviating activation of specific white blood cells.

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