A NATUrally Randomized trial Evaluating a vaccine-like strategy to lower LDL by inhibiting PCSK9 on the lifetime risk of major cardiovascular events (NATURE-PCSK9)

BackgroundMaintaining low levels of low-density lipoproteins (LDL) over time has the potential to substantially reduce the lifetime risk of atherosclerotic cardiovascular disease. However, the optimal timing of lowering LDL to prevent atherosclerotic cardiovascular events is unknown. MethodsWe combined evidence from Mendelian randomization studies and randomized trials to develop a causal AI algorithm to estimate the benefit of lowering LDL on the risk of major cardiovascular events (MCVE) in discrete time-units of exposure. We tested the accuracy of this algorithm among 440,371 participants randomized by nature to a partial loss-of-function (LOF) variant in the PCSK9 gene, and 46,488 participants in two large randomized trials of PCSK9 inhibitors. We then used this algorithm to estimate the benefit of lowering LDL using a once-yearly dose of an siRNA directed against PCSK9 beginning at different ages among 2.3 million men and women. ResultsThe causal AI algorithm accurately estimated the benefit of lifelong lower LDL due to partial loss-of-function of the PCSK9 gene, and the benefit of lowering LDL with a PCSK9 inhibitor starting at a mean age of 61 years, with nearly superimposable observed and predicted event curves. Lowering LDL by 36% was estimated to reduce the lifetime risk of MCVE by 57% (HR: 0.43, 95%CI: 0.39-0.47) if started at age 30, by 48% (HR: 0.52, 95%CI: 0.50-0.54) if started at age 40, by 38% (HR: 0.62, 95%CI: 0.60-0.65) if started at age 50, and by 26% (HR: 0.74, 95%CI: 0.71-0.77) if started at age 60 years. Moderate LDL lowering starting at age 40 years was estimated to have a greater benefit than more aggressively LDL lowering beginning at age 55 years, with a lower residual risk at all ages. In addition, the benefit of earlier LDL lowering persisted throughout life leading to a quantifiable legacy benefit. ConclusionsThe benefit of lowering LDL is determined by the magnitude, duration, and timing of LDL lowering. Modest sustained LDL lowering beginning in early to middle adulthood, which can be achieved with a once-yearly dose of a PCSK9 siRNA, may be the optimal strategy to prevent atherosclerotic cardiovascular events by slowing the progression of atherosclerosis.