The following question refers to Section 4.6 and Figure 13 of the 2021 ESC CV Prevention Guidelines. The question is asked by student doctorShivani Reddy, answered first by NPCarol Patrick, and then by expert facultyDr. Roger Blumenthal. Dr. Roger Blumenthal is professor of medicine at Johns Hopkins where he is Director of the Ciccarone Center for the Prevention of Cardiovascular Disease. He was instrumental in developing the 2018 ACC/AHA CV Prevention Guidelines. The CardioNerds Decipher The Guidelines Series for the 2021 ESC CV Prevention Guidelinesrepresents a collaboration with theACC Prevention of CVD Section, theNational Lipid Association, andPreventive Cardiovascular Nurses Association. Question #16 True or False: For patients with established ASCVD, secondary prevention entails adding a PCSK9 inhibitor if goal LDL is not met on maximum tolerated doses of a statin and ezetimibe. Answer #16 The correct answer is True. The ultimate on-treatment LDL-C goal of <55 mg/dL (<1.4 mmol/L) and a reduction of at least ≥50% from baseline should be considered for primary prevention of persons <70 years of age at very high risk (Class IIa) and in those with established ASCVD (Class I). It is recommended that a high-intensity statin is prescribed up to the highest tolerated dose to reach these LDL-C goals (Class I). The combination of statin with ezetimibe brings a benefit that is in line with meta-analyses showing that LDL-C reduction has benefits independent of the approach used. The beneficial effect of ezetimibe is also supported by genetic studies. Together, these data support the position that ezetimibe should be considered as second-line therapy, either on top of statins when the therapeutic goal is not achieved (Class I), or when a statin cannot be prescribed (Class IIa). PCSK9 inhibitors (monoclonal antibodies to PCSK9) decrease LDL-C by up to 60%, either as monotherapy or in addition to the maximum tolerated dose of statin and/or other lipid-lowering therapies, such as ezetimibe. Their efficacy appears to be largely independent of background therapy. Among patients in whom statins cannot be prescribed, PCSK9 inhibition reduced LDL-C levels when administered in combination with ezetimibe. Both alirocumab and evolocumab effectively lower LDL-C levels in patients who are at high or very high CVD risk, including those with DM, with a large reduction in future ASCVD events. Therefore, for those who do not meet LDL-C goals with maximally tolerated doses of both a statin and ezetimibe, combination therapy including a PCSK9 inhibitor may be considered for primary prevention of patients at very high risk but without familial hypercholesterolemia (Class IIa) and is recommended for secondary prevention for those with established ASCVD (Class I). In addition, for very-high-risk FH patients (that is, with ASCVD or with another major risk factor) who do not achieve their goals on a maximum tolerated dose of a statin and ezetimibe, combination therapy including a PCSK9 inhibitor is recommended (Class I). Main Takeaway Statins, ezetimibe, and PCSK9 inhibitors should be used in a stepwise approach to achieve target lipid lowering goals in accordance with their risk profile.