PCSK9 Inhibitors in Secondary Prevention-An Opportunity for Personalized Therapy

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Low-density lipoprotein cholesterol (LDL-C) is the primary cause of ASCVD and reducing LDL-C levels with statin therapy significantly reduces ASCVD risk; however, significant residual risk remains. Two monoclonal antibodies (mAbs), alirocumab and evolocumab, that target proprotein convertase subtilisin/kexin-type 9 (PCSK9), reduce LDL-C levels by up to 60% when used in combination with statins and significantly reduce the risk of recurrent ASCVD events in both stable secondary prevention and acute coronary syndrome populations. Prespecified analyses of recent randomized controlled trials have shed light on how best to prioritize these therapies to maximize their value in select high-risk groups. These data have also informed recent clinical practice guidelines and scientific statements resulting in an expanded role for PCSK9-mAbs compared with previous guidelines, albeit there are notable differences between these recommendations. Ongoing research is exploring the long-term safety of PCSK9-mAbs and their role in the acute setting and patients without prior myocardial infarction or stroke. Novel therapies that inhibit PCSK9 synthesis via small interfering RNA, such as inclisiran, are also in development and may reduce LDL-C levels similar to PCSK9-mAbs, but with less frequent administration. Nonetheless, the PCSK9-mAbs are a breakthrough therapy and warrant consideration in very high-risk patients who are most likely to benefit. Such a personalized approach can help to ensure cost-effectiveness and maximize their value.