[70] The more recent systematic review by Du et al. (2019) found that PCSK9 inhibitors reduced the risk of CV events (RR: 0.84, 95% CI: 0.79 0.89), non-fatal MI (RR: 0.83, 95% CI: 0.74 0.93), and any type of stroke (RR: 0.75, 95% CI: 0.65 0.85), with no effect on mortality.[68] Short-term (<3 years) safety data for PCSK9 inhibitors suggest no increased risk for new-onset DM,[79,82] no effect on neurocognitive function,[83] and no difference in serious adverse events. The only significant treatment-emergent adverse effect was injection site reactions, which were statistically higher for evolocumab and alirocumab versus control.[82,84,85] The long-term safety of these agents and the effect of prolonged levels of very low LDL-C is unknown. Thus, additional research is needed. In higher risk patients, there are several approaches that have been proven to reduce non-fatal CVD events compared to moderate-dose statins (see Table 1). However, there is no direct evidence to support the superiority of a single approach for intensification of lipid-lowering therapy between: a) maximizing statin dose; b) adding ezetimibe to moderate- or high-dose statin (in patients already on high-dose statins); or c) adding PCSK9 inhibitors to maximum-dose statin with or without ezetimibe Table 1. 