Several important questions need to be addressed by additional RCTs. 1. In secondary prevention, does a lower limit for LDL-C attainment exist, beyond which the incre- mental benefit attained is worth neither the risks nor the cost of additional therapy? 2. In secondary prevention, what are the indications for adding PCSK9 inhibitors to maximal statin therapy? 3. In patients with ASCVD who have statin-associ- ated side effects, are PCSK9 inhibitors an effective and safe substitute for high-intensity statins? 4. In primary prevention for adults 45 to 75 years of age (LDL-C <90 mg/dL [<2.3 mmol/L]) with or without diabetes mellitus, what is the incremental risk reduction imparted by high-intensity statins as compared with moderate-intensity statins? 5. In primary prevention for adults 45 to 75 years of age (LDL-C <190 mg/dL [<4.9 mmol/L]) with or without diabetes mellitus, what is the incremen- tal risk reduction imparted by moderate-intensity statins plus ezetimibe as compared with moder- ate-intensity statins alone? 6. Is statin therapy efficacious and safe in older patients (>75 years of age)? If so, what is a net benefit of statin therapy in this age group? 7. In patients with severe hypercholesterolemia, what are the efficacy and net benefit of PCSK9 inhibitors as add-on treatment to maximal statin therapy? 8. What is the efficacy of moderate-intensity and high-intensity statin therapy in patients with risk- enhancing factors (eg, chronic inflammatory dis- ease, CKD, metabolic syndrome)? 8.2. Risk Assessment In primary prevention, the appropriate selection of pa- tients for cholesterol-lowering drug therapy is highly de- pendent on risk assessment. Previous guidelines made Figure 3. Cost-effectiveness analysis for PCSK9 inhibitors. 