Similarly, studies of ezetimibe monotherapy and ezetimibe and statin combination therapy showing patient-oriented outcomes in primary prevention are lacking. While similar arguments can be made for bempedoic acid, icosapent ethyl, and PCSK9 inhibitors, their high cost and the large NNT for all therapies in primary prevention limit the potential cost-effectiveness of these medication classes in primary prevention at current prices. b. Secondary Prevention Patients with known CVD are at the highest risk of CV events. Since statins and ezetimibe are both generic and have proven benefit in this population when used in combination, the combination should be maximized and serve as the active control for evaluation of added efficacy and safety of newer therapies (bempedoic acid, icosapent ethyl, and PCSK9 inhibitors). Prospective studies evaluating the benefit of titrating lipid-lowering treatments to achieve specific LDL-C goals (e.g., <50, 70, 100 mg/dL) in patients at higher risk are lacking but would be helpful in determining the need for intensification of treatment to further reduce CV events. B. Effectiveness of Non-statin Monotherapy for Primary Prevention Most discontinuation of statin therapy is attributed to presumed statin myopathy. While many patients tolerate the same statin when re-challenged, some are reluctant to resume the same or different statin they presume caused the myalgias, leaving limited evidence-based medication options for primary prevention of CVD in patients who cannot take statins. There is a need for clinical trials of alternative lipid-lowering agents for CVD risk reduction in primary prevention populations. Current medications suitable for study would be ezetimibe, PCSK9 inhibitors, bempedoic acid, and icosapent ethyl. Because of the low cost of generic ezetimibe, studies of ezetimibe monotherapy for primary prevention would offer the highest potential benefit. 