Advances in targeting LDL cholesterol: PCSK9 inhibitors and beyond The relationship between LDL-C levels over a lifetime and cardiovascular events is direct. Statins remain the cornerstone of LDL-C lowering therapy due to their cost-effectiveness in reducing atherosclerotic events and mortality. However, global LDL-C goal attainment remains suboptimal, highlighting the need for non-statin therapies to address residual risk from statin intolerance, non-adherence, and inherited lipid disorders. Non-statin therapies include ezetimibe, PCSK9 monoclonal antibodies, inclisiran, and bempedoic acid, with specific guidelines for their use. For patients with homozygous familial hypercholesterolemia, lomitapide and evinacumab are available, offering mechanisms not dependent on LDL receptors. Lipoprotein apheresis is effective for familial hypercholesterolemia and elevated lipoprotein (a). Investigational therapies include CETP inhibitors, a third-generation PCSK9 inhibitor, and gene editing to directly modify genes. The article reviews pharmacotherapy options beyond statins for LDL-C lowering and their impact on ASCVD risk reduction. It aims to guide physicians in achieving appropriate LDL-C goals, with an algorithm for when to consider each therapy based on efficacy, safety, and outcomes. Statin therapy is effective in various populations, including women and those with diabetes. LDL-C lowering can be achieved by reducing cholesterol in LDL or enhancing its clearance. Dietary modification, regular physical activity, and weight reduction are first-line treatments for ASCVD risk reduction. The need for accurate lab measurement is emphasized, as LDL-C alone may not fully capture the atherogenic burden. ApoB and non-HDL-C are stronger indicators of atherogenicity than LDL-C alone. Statin therapy has been shown to reduce major adverse cardiovascular events, with a 22% reduction in MACE for every 38.7 mg/dL lowering in LDL-C. The concept of "lower for longer" is supported by evidence showing that early and prolonged exposure to lower LDL-C reduces ASCVD risk. The safety of very low LDL levels is discussed, with PCSK9 inhibitors showing benefits and safety at very low LDL-C levels. The safety of low LDL-C levels is supported by findings in individuals with genetically determined low levels of PCSK9 and LDL-C. The ODYSSEY OUTCOMES trial showed efficacy and safety at very low LDL levels, albeit for a short duration. The EBBINGHAUS study found no significant difference in cognitive performance scores in patients with very low LDL-C levels. The article discusses when to consider intensification of lipid-modifying strategies, emphasizing evidence-based approaches. Ezetimibe, bile acid sequestrants, bempedoic acid, PCSK9 inhibitors, and other therapies are reviewed, with specific guidelines for their use. The article also highlights the importance of shared clinician-patient decisionAdvances in targeting LDL cholesterol: PCSK9 inhibitors and beyond The relationship between LDL-C levels over a lifetime and cardiovascular events is direct. Statins remain the cornerstone of LDL-C lowering therapy due to their cost-effectiveness in reducing atherosclerotic events and mortality. However, global LDL-C goal attainment remains suboptimal, highlighting the need for non-statin therapies to address residual risk from statin intolerance, non-adherence, and inherited lipid disorders. Non-statin therapies include ezetimibe, PCSK9 monoclonal antibodies, inclisiran, and bempedoic acid, with specific guidelines for their use. For patients with homozygous familial hypercholesterolemia, lomitapide and evinacumab are available, offering mechanisms not dependent on LDL receptors. Lipoprotein apheresis is effective for familial hypercholesterolemia and elevated lipoprotein (a). Investigational therapies include CETP inhibitors, a third-generation PCSK9 inhibitor, and gene editing to directly modify genes. The article reviews pharmacotherapy options beyond statins for LDL-C lowering and their impact on ASCVD risk reduction. It aims to guide physicians in achieving appropriate LDL-C goals, with an algorithm for when to consider each therapy based on efficacy, safety, and outcomes. Statin therapy is effective in various populations, including women and those with diabetes. LDL-C lowering can be achieved by reducing cholesterol in LDL or enhancing its clearance. Dietary modification, regular physical activity, and weight reduction are first-line treatments for ASCVD risk reduction. The need for accurate lab measurement is emphasized, as LDL-C alone may not fully capture the atherogenic burden. ApoB and non-HDL-C are stronger indicators of atherogenicity than LDL-C alone. Statin therapy has been shown to reduce major adverse cardiovascular events, with a 22% reduction in MACE for every 38.7 mg/dL lowering in LDL-C. The concept of "lower for longer" is supported by evidence showing that early and prolonged exposure to lower LDL-C reduces ASCVD risk. The safety of very low LDL levels is discussed, with PCSK9 inhibitors showing benefits and safety at very low LDL-C levels. The safety of low LDL-C levels is supported by findings in individuals with genetically determined low levels of PCSK9 and LDL-C. The ODYSSEY OUTCOMES trial showed efficacy and safety at very low LDL levels, albeit for a short duration. The EBBINGHAUS study found no significant difference in cognitive performance scores in patients with very low LDL-C levels. The article discusses when to consider intensification of lipid-modifying strategies, emphasizing evidence-based approaches. Ezetimibe, bile acid sequestrants, bempedoic acid, PCSK9 inhibitors, and other therapies are reviewed, with specific guidelines for their use. The article also highlights the importance of shared clinician-patient decision