PCSK9 Inhibitors

PCSK9 inhibitors are lipid-lowering drugs that block proprotein convertase subtilisin/kexin type 9 (PCSK9), a proteolytic enzyme that indirectly regulates serum LDL cholesterol by causing the destruction of LDL receptors. ^[1] Evolocumab and alirocumab are two approved PCSK9 inhibitors, both fully human monoclonal antibodies that bind free PCSK9. ^[1] The clinically approved PCSK9 inhibitory therapies include three monoclonal antibodies (evolocumab, alirocumab, and tafolecimab) and one small interfering RNA, inclisiran. ^[2]

Inhibiting or binding circulating PCSK9 results in increased LDL receptors on liver hepatocytes, with a resultant decrease in serum LDL cholesterol. ^[1] Inclisiran is a small interfering RNA that prevents hepatic synthesis of PCSK9, thereby decreasing circulating LDL cholesterol, and is administered as a twice-yearly subcutaneous injection. ^[3] The effective half-life of evolocumab is 11 to 17 days, and its pharmacodynamic effects on PCSK9 are rapid, with maximum suppression within 4 hours. ^[4]

PCSK9 inhibitors have been found to achieve profound reductions in LDL cholesterol of 54% to 74% when added to statins, and have shown dramatic effects in lowering major adverse cardiovascular events in high-risk patients. ^[5] In clinical studies, doses of evolocumab reduced LDL cholesterol by approximately 55% to 75% compared with placebo and also reduced lipoprotein(a) levels. ^[4] In a network meta-analysis of 14 trials among 83,660 adults using statins, adding a PCSK9 inhibitor to statins reduced non-fatal myocardial infarction (relative risk 0.81) and stroke (relative risk 0.74) but not all-cause or cardiovascular mortality. ^[6] In very high-risk atherosclerotic cardiovascular disease patients whose LDL cholesterol remains at or above 70 mg/dL on maximally tolerated statin and ezetimibe therapy, guidelines state that adding a PCSK9 inhibitor is reasonable. ^[7]

PCSK9 inhibitors produce minimal side effects, and myopathy, a common side effect for patients on statins, has been rare in patients on PCSK9 inhibitors. ^[5] Long-term inhibition of PCSK9 with monoclonal antibodies is safe and conveys sustained cardiovascular benefit, supported by follow-up data of up to 8 years of exposure. ^[8] The benefit of adding a PCSK9 inhibitor is concentrated in higher-risk patients: among adults at moderate and low cardiovascular risk, adding a PCSK9 inhibitor to statins yielded little or no benefit for myocardial infarction and stroke. ^[6]