Advancements in lipid-lowering therapy: the role of proprotein convertase subtilisin/kexin type 9 inhibitors and beyond in cardiovascular risk reduction

Atherosclerotic cardiovascular disease (ASCVD) is a leading global cause of death. Although statins are the foundation of lipid-lowering therapy, many high-risk patients fail to achieve low-density lipoprotein cholesterol (LDL-C) targets due to intolerance or insufficient response. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as potent agents that address this residual risk. This review summarizes the clinical efficacy, safety, and mechanistic role of PCSK9 inhibitors in cardiovascular risk reduction. Relevant randomized trials, meta-analyses, and observational studies were analyzed, alongside emerging nonstatin therapies including bempedoic acid, inclisiran, and Angiopietin-like 3 inhibitors. PCSK9 inhibitors, such as alirocumab and evolocumab, have shown LDL-C reductions of up to 62% and significant decreases in major adverse cardiovascular events. Trials like Further cardiovascular outcomes research with PCSK9 inhibition in subjects With elevated risk (FOURIER) and Evaluation of cardiovascular outcomes after an acute coronary syndrome during treatment with alirocumab (ODYSSEY OUTCOMES) reported relative risk reductions of 15-24% in select populations. These agents also reduce lipoprotein(a) (Lp(a)) and stabilize atherosclerotic plaques. Additional therapies like inclisiran and bempedoic acid further expand treatment options, particularly for statin-intolerant patients. PCSK9 inhibitors offer a well-tolerated and effective approach to lowering LDL-C and mitigating cardiovascular risk. Their integration, along with emerging therapies, provides a comprehensive strategy to address residual ASCVD risk and improve patient outcomes. This review highlights the pivotal role of PCSK9 inhibitors in achieving significant LDL-C reduction and improving cardiovascular outcomes, especially in high-risk and statin-intolerant populations. By also targeting Lp(a) and promoting plaque stabilization, these agents address multiple contributors to residual ASCVD risk. Incorporating PCSK9 inhibitors and emerging nonstatin therapies into clinical practice offers a powerful strategy to enhance long-term cardiovascular prevention.