This recommendation highlights the research deficits for the use of ezetimibe for primary prevention. Since providers often consider the use of ezetimibe in patients who cannot tolerate statins, the lack of evidence for ezetimibe as monotherapy for primary prevention is a significant knowledge gap. Despite the lack of evidence for significant harm from statins, press coverage is replete with articles suggesting safety concerns with statins. This negative coverage contributes to patient apprehension toward statins, which was noted by patient focus group participants. If benefit with ezetimibe monotherapy in primary prevention could be proven, providers would have more options. Recommendation 10. For primary prevention, we recommend against offering PCSK9 inhibitors due to unknown long- term safety, inconclusive evidence for benefit, and high cost. (Strong against | Reviewed, New-added) Discussion The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been studied primarily for secondary prevention of CV events, but trials have included some primary prevention patients. A systematic review by Du et al. (2019) included 10,225 primary prevention patients from studies involving PCSK9 inhibitors with and without statins and failed to demonstrate significant improvements in CV events or mortality.[68] In fact, no important CV outcome showed significant improvement from PCSK9 inhibitors when used for primary prevention. The authors of this review reported they did not have individual trial data, so they could not separate trials that combined primary and secondary prevention. The FDA approved PCSK9 inhibitors for primary prevention in FH based solely on the effect of lipid parameters in this population. None of the studies were designed to measure CV outcomes. The ODYSSEY LONG TERM trial did perform a post hoc analysis of a combination of secondary prevention and FH patients that showed benefit but did not separate the primary and secondary prevention populations.