Each decade earlier of starting LDL-c lowering associated with stepwise increase in lifetime CV risk reduction

Nature-PCSK9: A NATUrally Randomized ‘target’ trial Evaluating a yearly vaccine-like strategy to lower LDL by inhibiting PCSK9 on the lifetime risk of major coronary events

News - Aug. 31, 2021

Presented at the ESC congress 2021 by: Prof. Brian Ference, MD - Cambridge, UK

Introduction and methods

It is suggested that LDL-c lowering early in life can substantially reduce lifetime risk of CV events, by slowing the progression of atherosclerosis. Indeed, Mendelian randomization studies show that long-term exposure to lower LDL-c is associated with greater reduction of CV events compared to lowering LDL-c later in life.

The availability of a once-year dose of siRNA against PCSK9, that reduces LDL-c by 36%, allows for the use of a vaccine-like strategy to lower LDL-c and reduce lifetime risk of CV events. Optimal timing and age to begin with LDL-c lowering are unknown.

The aim of this study was to compare the effect of a yearly vaccine-like strategy to lower LDL-c using an siRNA directed against PCSK9 beginning at ages 30, 40, 50, or 60 compared to usual care on lifetime risk of major coronary events.

The secondary aim was to empirically examine whether the benefit of LDL0-c lowering beginning at any age and lasting for any duration is proportional to the cumulative decrease in LDL-c (the cumulative exposure hypothesis).

To study these aims, a naturally randomized ‘target’ trial was used; an extension of the concept of a ‘target’ trial using real world evidence by introducing randomization and the ability to study novel therapies with prolonged follow-up time. The benefit of LDL lowering by inhibiting PCSK9 with an siRNA on the lifetime risk of major coronary events beginning at any age was estimated using the PCSK9 genetic variants that the siRNA mimics.

The study population consisted of 445,754 participants in the UK Biobank without history of CVD, diabetes or cancer before age of 30 years. Those with LDL-c > 5 mmol/L were excluded. The primary outcome was lifetime risk of major coronary events (MC, fatal or non-fatal MI or coronary revascularization).

Main results

  • In an independent sample of 60,801 CAD cases and 123,504 controls, Mendelian randomization study showed that lower LDL-c measured in mmol-years exactly predicted the lifetime risk of coronary events at all ages among participants with lifetime exposure to lower LDL-c due to randomized inheriting PCSK9 partial loss of function or due to a combination of genetic variants.
  • Similarly, lower LDL-c measured in mmol-years precisely predicted the benefit from lowering LDL-c with a monoclonal antibody against PCSK9 during each month of follow-up in both the FOURIER trial and ODYSSEY trial.
  • Analysis showed a stepwise increase in the proportional reduction in lifetime risk of CV events with each earlier decade that LDL-c lowering was started by inhibiting PCSK9 with one-yearly dose of siRNA. For example, starting treatment in men at age 60 was associated with a 27% reduction in lifetime risk, while starting treatment at 30 was associated with a 52% reduction.
  • 36% Reduction in LDL-c with one yearly PCSK9 siRNA beginning at age 40 was associated with greater expected reduction in lifetime risk at all ages compared to 52% reduction in LDL-c with twice-yearly PCSK9 siRNA started at 55 years.
  • Individuals with higher baseline LDL-c levels had a greater expected proportional reduction in lifetime risk in response to PCSK9 siRNA to lower LDL-c at all ages compared to individuals with lower baseline LDL-c levels. However, all individuals had large expected reduction in lifetime risk, even those with LDL-c levels ≤2.6 mmol/L, and had stepwise greater expected reductions in lifetime risk with each decade earlier that LDL-c lowering was started.


First, the cumulative exposure hypothesis for LDL-c was confirmed. Then, it was shown that each decade earlier of initiation of LDL-c lowering by a one-yearly dose of an siRNA against PCSK9 is associated with a stepwise proportional increase in reduction of lifetime risk of major CV events. Modest reductions in LDL-c beginning earlier in life are associated with a greater reduction in lifetime risk compared to more intensive LDL-c lowering starting later in life.

Prof. Ference suggested that residual risk of CV events appears to be largely due to the cumulative exposure to LDL-c prior to the initiation of LDL-c lowering.

- Our reporting is based on the information provided at the ESC Congress -

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