I think one overlooked aspect of translating genetic estimates of Lp(a)-lowering into expected clinical benefit is the difference in LDL-C and Lp(a) trajectories across the lifespan. The estimates for Lp(a)-lowering are derived by extrapolating from how the effect of genetically lowered LDL-C on cardiovascular risk translates to MACE risk reductions in trials. LDL-C increases substantially with age, whereas Lp(a) remains largely stable over the lifetime. If we accept that atherogenesis is driven by cumulative exposure to atherogenic particles over time (“particle-years”), then the effect of Lp(a)-lowering over the same period should be smaller than the effect of LDL-C-lowering. A given reduction in Lp(a) represents a smaller proportion of lifetime cumulative exposure because Lp(a) levels are relatively high earlier in life, whereas LDL-C exposure accumulates progressively with age. This was not accounted for in the estimates used for the power calculations of Lp(a)HORIZON, which were partially based on genetic estimates derived through this LDL-C → Lp(a) extrapolation. This could be one reason why the eventual clinical effect of Lp(a)-lowering is smaller than expected.