The NATURE-PCSK9 study revealed that a yearly vaccine-like approach with PCSK9 small-interfering RNA can reduce cardiovascular events by up to two thirds. The motto ‘the earlier the better’ also holds true for low-density lipoprotein (LDL) reduction1.
Individuals who inherit LDL-lowering variants in the PCSK9 are known to have large reductions in lifetime risk of cardiovascular events. In a previous study, a single dose of a PCSK9 small-interfering RNA (siRNA) led to a durable reduction of LDL concentrations over 1 year ranging from 29.5% to 38.7% . “The availability of a yearly dose of siRNA directed against PCSK9 allows us to use this strategy in a vaccine-like approach,” explained Prof. Brian Ference (University of Cambridge, UK).
The primary objective of the NATURE-PCSK9 study was to compare the potential clinical benefit of a yearly vaccine-like strategy using siRNA beginning at age 30, 40, 50, or 60 years (expected to result in a 36% LDL reduction) with usual care on the lifetime risk of major coronary events. “Ideally, this would be done in a randomised controlled trial, but this is not feasible over a time period of 50 years,” Prof. Ference said. Thus, the NATURE-PCSK9 trial estimated the clinical benefit and optimal timing of a PCSK9 siRNA vaccine-like strategy using data from the PCSK9 variants that the siRNA was designed to mimic to anticipate the expected outcome.
Included in the analysis were 445,765 participants enrolled in the UK Biobank without a diagnosis of atherosclerotic CV disease, diabetes, or cancer before the age of 30 years. The cumulative exposure to lower LDL in mmol-years precisely predicted the observed benefit from lifelong lower LDL due to PCSK9 partial loss of function, but also the benefit observed from lowering LDL with a PCSK9 inhibitor confirming the cumulative exposure hypothesis for LDL.
The vaccine-like strategy to lower LDL had the potential to dramatically reduce the lifetime risk of cardiovascular events by up to two-thirds – depending on baseline LDL and age at which therapy is started. Each decade earlier that LDL lowering was initiated was associated with an increasingly greater proportional reduction in lifetime risk. A hazard ratio [HR] of 0.48 was calculated when LDL lowering began at 30 years of age, an HR of 0.54 for LDL lowering beginning at 40 years, an HR of 0.63 for LDL lowering from 50 years, and an HR of 0.73 for LDL lowering from 60 years. Moreover, patients with greater baseline LDL had a greater effect. Similar stepwise increased reductions in the lifetime risk of major CV events and the individual components of the composite outcomes were observed with each decade of earlier initiation of LDL-lowering therapy for both men and women.
The NATURE-PCSK9 study found that a vaccine-like strategy to reduce LDL using a once-yearly dose of a PCSK9 siRNA can markedly reduce the lifetime risk of CV events; the effect being greater the earlier the LDL-lowering siRNA therapy is initiated.
1. Ference B. NATURE-PCSK9: A NATUrally Randomized ‘Target’ trial Evaluating a yearly vaccine-like strategy to lower LDL by inhibition PCSK9 on the lifetime risk of major coronary events. Late-breaking trials in prevention, ESC Congress 2021, 27 - 30 August.
2. Ray KK, et al. JAMA Cardiol 2019;4:1067–75.