In light of the recent decision by the UK health authorities to approve inclisiran for use in patients, I thought it would be interesting to delve in to how good the class of drugs it belongs to, the PCSK9 inhibitors, really are. PCSK9 inhibitors can be thought of as “next generations statins”. Like statins, they work under the assumption that the lipid transport molecule LDL (often incorrectly referred to as “bad cholesterol”) is the main driver of cardiovascular disease, and their goal is thus to lower LDL levels in the bloodstream.
Unlike statins, however, they work in a much more direct fashion, which should resut in significantly less side effects. Statins inhibit the ability of cells to produce cholesterol (a molecule that is critical for the correct functioning of cell membranes and for the production of many hormones), and through a sequence of downstream effects, this results in the liver hoovering up more LDL from the blood stream. PCSK9 inhibitors instead work in a much less roundabout way to increase the number of receptors on the surface of liver cells that pluck LDL from the blood stream.
In theory, as mentioned, this should result in significantly less side effects, since the side effects seen with statins, such as muscle pain and weakness, likely for the most part have to do with impaired cholesterol synthesis, and PCSK9 inhibitors don’t impair cholesterol synthesis. This more targeted and side-effect free mechanism should then allow for higher dosing, which should cause LDL to drop lower than is possible with statins. This should then result in less heart attacks and strokes.
PCSK9 inhibitors are new drugs and thereby still on patent and hugely expensive. Additionally, the PCSK9 inhibitors that have so far been developed are all broken down in the intestine if ingested, which means they can’t be given as a pill – they need to be injected. That means they’re not going to replace statins as the main LDL lowering drug any time soon. But if they can be shown to actually lower cardiovascular events and prolong life, and especially if new PCSK9 inhibitors are developed that can be taken as a pill, then it’s quite likely that they will eventually come to replace statins as the main LDL lowering drug.
Ok, let’s get to the evidence. An observational study was published in the New England Journal of Medicine in 2006 that provided support for the idea that PCSK9 inhibiting drugs might be effective at preventing heart disease. 12,973 people in the US were followed for 15 years to see if they developed cardiovascular disease. The participants were tested to see if they had a normal PCSK9 gene (which results in normal recycling of the LDL receptor on liver cells, and thus normal levels of the receptor) or if they had a defective gene (resulting in defective recycling and thus higher levels of the LDL receptor on liver cells). 97% had the normal gene, while 3% had an abnormal version of the gene.
As would be expected, those with the defective genes had lower levels of LDL in the blood stream, 21% lower to be precise. More importantly, they also experienced less heart disease. A lot less. While 11% of those with the normal gene developed heart disease over the fifteen year follow-up period, only 5% of those with an abnormal gene developed heart disease.
When it comes to stroke there was no difference, however, with 4% experiencing a stroke in each group. This is surprising at first glance, but could perhaps be explained by the fact that strokes often aren’t caused by LDL induced damage to the vascular wall, but rather by other things, such as atrial fibrillation, artery dissections, and intracranial bleeds.
In terms of overall mortality, there was a small benefit seen, with 12.5% dying in the group with the normal PCSK9 gene over 15 years, as compared with 9.6% in the group with the defective gene. The difference in mortality didn’t reach statistical significance however (which of course doesn’t mean it wasn’t real, just that there weren’t enough deaths overall to be able to tell if the difference was real or not).
This was an observational study, so it’s impossible to draw firm conclusions about cause and effect. The study was therefore suggestive of a health benefit associated with inhibiting PCSK9, but it didn’t prove anything. Nevertheless, the massive reduction in heart disease seen in the study led to a frenzy among drug companies to develop PCSK9 inhibiting drugs. There are now three such drugs authorized for use in patients: evolocumab, alirocumab, and inclisiran.
So, how well do they work?
A systematic review and meta-analysis was published by the Cochrane Collaboration in October 2020 that sought to answer this question. It looked specifically at evolocumab and alirocumab (inclisiran wasn’t yet approved for use in patients). 24 randomized controlled trials, with a total of 60,997 participants, were included in the review. It’s worth keeping in mind that all but one of the trials was industry sponsored, which means that we can be pretty sure that whatever the results turn out to be, they are a best case scenario. Industry sponsored trials usually overestimate benefit (and underestimate harm).
The trials varied in length from six months to three years, which is a bit short if you want to detect a meaningful difference in heart attacks, and especially if you want to detect a meaningful difference in mortality. The observational study described above ran for fifteen years, and although there was a clear difference in heart disease, the difference in overall mortality wasn’t statistically significant. That’s another thing that’s worth keeping in mind as we get to the results – if the studies fail to find a mortality benefit, the reason might simply be that the follow-up period was too short, not that they don’t work. I do think, however, that a good general principle is to assume that drugs don’t work until it’s been proven otherwise.
Let’s get to the results.
Nine trials, with 23,352 participants, looked at the ability of alirocumab to prevent heart attacks. 9.8% of participants in the alirocumab group had a heart attack, compared with 12.5% in the placebo group. That is a 22% relative risk reduction, and it is statistically significant. Considering the short follow-up period, that’s actually not too bad. It would mean that you would need to treat 37 people for somewhere between six months and three years to prevent one heart attack.
Three studies, with 29,432 participants, looked at the ability of evolocumab to prevent heart attacks. 3.2% of the participants in the evolocumab group had a heart attack, compared with 4.5% in the placebo group. That’s a 29% reduction in relative risk. Again, the difference was statistically significant.
Let’s look at at overall mortality, which is after all what matters most. When it comes to alirocumab we see that 2.6% died in the alirocumab group compared with 3.6% in the placebo group, and when it comes to evolocumab we see that 3.0% died in the evolocumab group compared with 3.0% in the placebo group.
Hmm… So, basically alirocumab appears to result in a massive 28% reduction in risk of death, while evolocumab doesn’t appear to impact risk of dying at all. That is odd. Considering how large a number of participants the trials have gathered, and that the drugs basically function in exactly the same way, and that the effect on heart attacks is similar, you would expect the effect on overall mortality to be similar. Yet one results in a massive drop in overall mortality and the other doesn’t affect mortality at all. Which result is to be believed?
To be honest, I think the difference might simply be due to differences in luck and above all patient selection. 12.5% of patients in the placebo group in the alirocumab trials had a heart attack, compared with only 4.5% in the evolocumab trials – clearly the participants in the alirocumab trials were sicker to begin with, which would have increased the odds of finding a difference in mortality.
My guess is that both drugs probably do result in a reduction in overall mortality. If you compare the confidence intervals for the two drugs you find that there is some overlap, at between a 9% relative risk reduction at best for evolocumab and a 4% relative risk reduction at worst for alirocumab. The true benefit is probably somewhere in that overlap. If we assume the relative risk reduction is halfway between those two numbers – 6.5% – that would mean someone with a 3% risk of dying over the next few years could decrease the risk to 2.8%.
Impressive? Or not? Well, it would mean that you would need to treat 500 people for a few years to prevent one death. Which isn’t very impressive at all. It’s possible that the benefit increases over time, but it’s also possible that it stays at the same level or even diminishes over time. Without any long term follow-up it’s impossible to know. And the studies were virtually all industry funded, so the real world benefit may well be smaller.
What about the third PCSK9 inhibitor, inclisiran, that’s just been approved in the UK?
Two trials, with a total of 3,178 participants, were published in the New England Journal of Medicine in April 2020. Participants received inclisiran or placebo and were followed for 18 months. So, what did the researchers find?
1.8% of people had a heart attack in the inclisiran group, compared with 2.5% of people in the placebo group. Not bad, especially when you consider that the trials only ran for a year and a half. The relative risk reduction is 28%, which is similar to what the studies of alirocumab and evolocumab found.
If we look instead at overall mortality, we see that 1.6% of participants died in the inclisiran group, compared with 1.9% of people in the placebo group. Again, not bad for such a short follow-up if real, since it represents a 16% reduction in the relative risk of dying, but the small number of participants in the study means the result isn’t statistically significant. It is thus impossible to say whether it’s real or not.
Ok, what can we conclude from all this?
People who take PCSK9 inhibitors appear to lower their relative risk of a heart attack by somewhere between 20% and 30%. Whether that is a meaningful difference or not in real terms will depend on your starting risk. For someone at high risk of a heart attack, it might be useful to take a PCSK9 inhibitor. For someone at low risk, the benefit will be negligible.
There is still too little evidence available on PCSK9 inhibitors to be able to determine whether they can actually prolong life, although there is a suggestion of a small benefit. As mentioned earlier, the results presented here should be viewed as best case scenarios since virtually all the evidence comes from pharmaceutical companies. Maybe in another twenty years there will be some large independent studies done and we’ll know for sure how effective these drugs are.