LDL-c: new insights into its role as causal risk factor and target for therapy

Good afternoon. I should begin by thanking our host PACE , as well as the sponsors for inviting me. It's a real pleasure to be here. These are my disclosures.

Recently, there have been developments in our understanding of the biology of atherosclerosis in combination with the developments of innovative therapies and novel analytical methods that really allow us for the first time to begin to reimagine how we can dramatically reduce the risk of atherosclerotic cardiovascular disease by targeting LDL. As all of you know, a consensus is emerging that atherosclerosis is caused by the trapping of LDL and other apoB-containing lipoproteins within the artery wall. As more particles become trapped in the artery wall, the plaque grows and our risk increases.

This simple and intuitive understanding, the biology of atherosclerosis, gives rise to the cumulative exposure hypothesis. This hypothesis suggests that our underlying plaque burden is a function of our total cumulative exposure to LDL. The more particles we trap, the larger our underlying plaque burden grows and the higher our risk. What's interesting is that this cumulative exposure hypothesis precisely explains how risk evolves over time. Beginning early in life, as particles become trapped within the artery wall, the plaque grows, but the underlying plaque burden is still quite small so that even if it is disrupted, the overlying thrombus wouldn't occlude the vessel to increase the risk of cardiovascular events. Early in life, as plaque grows, the risk of having an acute cardiovascular event is low. However, once we reach a certain cumulative exposure, the underlying plaque burden is now large enough so that if a plaque did disrupt, the overlying thrombus could occlude the vessel. At this point, the risk of having an acute cardiovascular event becomes measurable. As we continue to trap particles in the artery wall and the plaque grows over time, the risk of having an acute cardiovascular event increases exponentially with age.Age really has nothing to do with our risk of having an atherosclerosis event. It is merely a marker of our cumulative exposure.

The main implication of the cumulative exposure hypothesis is that lowering LDL beginning earlier in the course of the disease can potentially dramatically reduce the lifetime risk of cardiovascular disease by changing the trajectory of atherosclerosis, reducing and slowing the rate at which we trap apoB-containing lipoproteins, delaying the age at which we develop a large enough atherosclerotic plaque burden that we're at risk for an acute coronary event if the plaque does disrupt.

Indeed, there is a great deal of randomized evidence to support the cumulative exposure hypothesis, particularly for Mendelian randomization studies. We know that people who are randomized by nature to lifelong lower LDL have dramatically lower lifetime risk of cardiovascular event. What's interesting is that the magnitude of that reduction per unit lower LDL is at least two or threefold greater than the observed reduction in risk, for the same magnitude of LDL reduction observed at randomized trials suggesting that LDL has both a causal and accumulative effect on the lifetime risk of cardiovascular events. Indeed, even modest reductions in LDL have the potential to dramatically reduce our lifetime risk. It's been estimated for Mendelian randomization studies in naturally randomized trials by mother nature herself that if we were able to maintain our LDL levels just a mmol lower and 10 points lower blood pressure to protect the artery wall from accumulating irreversible injury, we could reduce our lifetime risk of cardiovascular events by up to 80%, reduce cardiovascular mortality by two-thirds and reduce all-cause mortality by one third.

Indeed, it's been suggested if we had a safe and convenient method to reduce our LDL by 50% or more, regardless of how we do it, regardless of the mechanism, so long as we're producing a proportional reduction, the apoB-containing lipoproteins, we could really dramatically reduce our lifetime risk of cardiovascular disease and potentially even make atherosclerosis rare.

It turns out those therapies are now being developed. Recently, several therapies, the siRNA therapies directed against PCSK9, which are designed explicitly to recapitulate partial loss of function variants of nature to safely and potently reduce LDL have been developed. What's quite remarkable is that these therapies when given just once a year can produce sustained time average reductions of 35% or more. The availability of this once-yearly dose of an siRNA directed against PCSK9 offers the potential for a vaccine-like strategy to lower LDL and therefore substantially reduce the lifetime risk of cardiovascular events by slowing the progression of atherosclerosis if we intervene early in the course of disease.

The question, of course, becomes, who should we target? After all, we can't simply give the medicine to everybody. We know, for example, that when mother nature randomizes people to partial loss of function variants in PCSK9 gene, they have lower lifetime exposure to LDL and a correspondingly lower lifetime risk of cardiovascular events. Similarly, when we give people antibodies to lower LDL by inhibiting PCSK9 in trials, we can reduce their risk of cardiovascular events. The question is, how do we estimate every area in between? After all, Mendelian randomization studies only estimate the benefit of lifelong exposure to lowering LDL beginning at birth while trials only estimate the benefit of lowering LDL for a few years beginning late in life after atherosclerosis has already developed. Recently, new analytical methods have been developed that allow us to capture the causal effect of LDL in discrete time units of exposure, conditional on previous exposure to reflect the underlying biology of atherosclerosis, of how atherosclerosis develops. When we apply these algorithms, what we see is something quite remarkable. We can precisely predict the risk of having a cardiovascular event at any age among those people naturally randomized to lower LDL by inhibiting PCSK9 with a partial loss of function variant, as well as precisely predict the benefit of lowering LDL by inhibiting PCSK9 with an antibody during every single month of follow-up in the randomized trials.

The fact that we now have analytical tools available that allow us to precisely predict the benefit of lowering LDL over the lifetime, as well as the benefit of lowering LDL during every month of the therapy allows us for the first time to begin to contemplate having a strategy to identify the optimal timing, dosage, intensity, and duration of therapy to reduce the risk of cardiovascular events. When we conduct these experiments, what we see is that indeed, each decade earlier that we start to lower LDL is associated with a corresponding stepwise reduction in the risk of cardiovascular events for the same reduction in LDL, strongly supporting the cumulative exposure hypothesis. What is perhaps even more interesting is that we can begin to compare the strategies of a once-year vaccine-like strategy with an siRNA directed against PCSK9 beginning at age 40, earlier in life, as compared to a twice-a-year strategy of siRNA directed against PCSK9 beginning later, say at age 55. When we do this experiment, what we see is that more modest sustained reductions early in life with a once-year PCSK9 dose are associated with a lower remaining lifetime risk of cardiovascular events at all ages, as compared to the more aggressive twice-a-year 50% reduction in PCSK9 started at age 55. This confirms that earliest modest sustained reductions in LDL is a much more effective strategy at reducing cardiovascular events as compared to a more potent LDL reductions beginning later in life. It also reveals an important biological insight. It suggests that the higher residual risk of having new cardiovascular events, even among those people who are in potent LDL lowering therapies to lower their LDL by 50% or more, is due to the accumulated plaque burden that occurs before we initiate lowering LDL therapies. Lowering LDL beginning earlier in life to change the trajectory of atherosclerosis not only can dramatically reduce the lifetime risk of cardiovascular disease, but it can potentially solve the mystery of residual risk.

Now, it isn't just siRNAs, of course. There are many other therapies currently in development all with the goal of producing safe ways to sustainably reduce LDL in a way that ensures compliance so that we can invite people for 30 or 40 or 50 or even 60 years to participate in their health.

In conclusion, I would suggest that there is really now the opportunity to reimagine the prevention of atherosclerosis because atherosclerosis is clearly caused by progressive trapping of LDL and other apoB-containing lipoproteins within the artery wall, and it is this cumulative exposure to LDL that determines our plaque burden. Our plaque burden is the main determinant of our risk, and therefore, LDL has both a causal and a cumulative effect and it is imperative that we lower beginning much earlier in life. It also implies that the benefit of lowered LDL depends on the magnitude, the duration and the timing of that LDL lowering. Now with the availability of novel therapies that can ensure compliance, we have the opportunity to think about intervening much earlier to produce sustained dramatic reductions in LDL to change the course of atherosclerosis. If we combine these novel therapies and these novel insights with novel analytical tools that embed causal effects of LDL discrete time-units of exposure to reflect how atherosclerosis develops, it can begin to not just predict but to prescribe the optimal timing, duration, and magnitude of lowering LDL for each person, making it possible to reimagine the prevention of cardiovascular disease and introduce the era of precision in population health. Thank you.