Next-generation PCSK9 inhibitors: clinical evidence and future directions for cardiovascular prevention

Low-density lipoprotein cholesterol (LDL-C) is a causal and modifiable risk factor for atherosclerotic cardiovascular disease, and intensive reduction of LDL-C is central to prevention strategies. Meta-analyses have shown that each 1 mmol/L (approximately 38.7 mg/dL) decrease in LDL-C confers about a 22% relative risk reduction in major vascular events, independent of baseline LDL-C levels. Despite the proven efficacy of statins and ezetimibe, many patients fail to reach recommended LDL-C targets due to inadequate response, intolerance, or poor adherence to daily therapy. The development of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has transformed lipid management, providing substantial LDL-C reduction. Recently, next-generation agents with extended dosing intervals have emerged, including recaticimab, a fully human monoclonal antibody, and inclisiran, a small interfering RNA therapy. Recaticimab binds circulating PCSK9, preventing degradation of the low-density lipoprotein receptor, and achieves sustained LDL-C reductions of about 50% with dosing every 8 to 12 weeks. Inclisiran employs N-acetylgalactosamine (GalNAc)-mediated hepatocyte delivery to silence PCSK9 messenger RNA, producing comparable LDL-C reductions with twice-yearly maintenance dosing after an initial loading dose. Their extended dosing schedules offer potential benefits in adherence and long-term lipid control, particularly for high-risk patients who struggle with frequent dosing or have statin intolerance. As outcome data accumulate, these therapies may further reduce residual atherosclerotic cardiovascular disease risk and become increasingly important in comprehensive prevention strategies.