Current and emerging PCSK9‐directed therapies to reduce LDL‐C and ASCVD risk: A state‐of‐the‐art review

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Lowering low-density lipoprotein cholesterol (LDL-C) levels is a primary strategy to reduce ASCVD risk. Although statin therapy remains the initial therapy of choice to reduce LDL-C and ASCVD risk, statin intolerance and suboptimal LDL-C lowering response prompts the need for additional non-statin therapies. Ezetimibe and bempedoic acid are reasonable options but they modestly reduce LDL-C levels (15% to 25%). Therapies directed at the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, however, reduce LDL-C levels by 50%-60% when added to background statin therapy. PCSK9 is an enzyme synthesized by the liver that facilitates the degradation of LDL receptors and prevents their recycling to the hepatocyte surface to remove LDL-C from circulation. Approaches to inhibit this effect have centered on monoclonal antibodies (mAbs) (alirocumab, evolocumab) targeting PCSK9 functionality and small interfering RNA (siRNA) therapies (inclisiran) targeting the hepatic synthesis of PCSK9. Randomized controlled trials have demonstrated beneficial cardiovascular outcomes of PCSK9 mAbs, but such evidence is not yet available for inclisiran. Current clinical practice guidelines generally recommend PCSK9-directed therapies for higher-risk patients with established ASCVD and those with familial hypercholesterolemia. This approach is, in part, due to their cost and uncertain economic value, but also because these therapies require subcutaneous administration, which is not preferred by some patients. Oral therapies targeting PCSK9 are, however, in development. This scoping review covers the development of current and emerging PCSK9-directed therapies, their efficacy, safety, and role in clinical practice.