Today we'll speak about triglycerides. Is it getting messy? These are my disclosures.

Well, we have to move away. Why? This is the data from the FOURIER open-label extension. You can actually see that after prolonged inhibition, we see mortality reduction, so LDL reduction is brilliant, but look what happened. We're currently all the way down to the LDL curve. After we've done this, LDL is finished, gone. Unfortunately, we still have a white marked residual cardiovascular risk, so we have to refocus.

There's a lot of options and all success, so it's a success story. There are some issues we take into account. For instance, for Lp(a), we're waiting the evidence, for intensification of anticoagulation, whoa, think of the bleeding, in anti-inflammatory therapy, whoa, think of the infection. This middle part, remnant cholesterol, triglycerides, and metabolic burden is very attractive with very few downsides.

Actually, do we know what high triglycerides are? Well, this is the picture of the metabolites in the triglyceride metabolism. Here you see large VLDL, the IDL, which is now let's say, the cholesterol remnants or triglyceride-rich lipoproteins. Somewhere in this heterogeneous fraction there is something about atherogenesis. Do we know this for sure?

I think the nicest is to go back in history. What have we learned? Here you can see that triglyceride-rich lipoproteins, they actually split off of fatty acids, they become remnants. Then remnants can actually through transcytosis and paracellular transport can get into the sub-endothelial space, where they can be engulfed by macrophages without any need for any receptor. Mind you, these remnant particles have up to five times more cholesterol than any individual LDL cholesterol particle. It's not innocent because triglyceride-rich remnants carry a quite significant load of cholesterol. Let's go back to Anichkov in the early 19th century, where Anichkov actually performed an experiment, where he fed eggs to rabbits. The cholesterol of this eggs is transported in the triglyceride-rich lipoproteins and chylomicron remnants. What he showed and Zilversmit did with elegant labeled cholesterol experiments to show that indeed the cholesterol fat ends up for a substantial part in the sub-endothelial space, contributing to atherogenesis. Yes, they are atherogenic.

What about the epidemiological evidence? Well, here you can see a meta-analysis and you can see postprandial impact. Yes, triglycerides, both fasting and non-fasting contribute to an increased cardiovascular risk.

What about genetics? Is it causal? Well Brian Ference was instrumental. Yes, all the triglyceride apoB-containing particles do contribute to atherogenesis. It's the number of particles it's driving the atherogeneity.

Now the complication, whenever you speak to cardiologists about high triglycerides, they think it's the same as LDL. One LDL particle, one risk, one hypertriglyceridemia, one risk, but that's not the case. These are both patients where triglycerides are 4.5 mmol/L. On the left, a lot of smaller particles with a lot of cholesterol. On the right, the large VLDL particles predominantly containing triglycerides and much less cholesterol esters. What is hypertriglyceridemia? We have to think particles, and not only the term because it's the cholesterol burden hidden in these particles which contributes to atherogenesis.

Here you can see some typical examples, all hypertriglyceridemia. If you look, the particles are different, and the atherogenic risk will be different. Here the one with high apoB, high number of particles, this is where the atherogenesis risk is.

We've known this for decades. This is data from the Framingham Heart Study. Can you still remember? That's long ago. Look at the above lines. If you have non-HDL or triglyceridemia, if you have high levels, but low apoB, there's hardly an impact on cardiovascular events. If you have high levels on the high apoB, there is a profound impact on cardiovascular risk. This is an old lesson revisited.

What about the intervention trials? Here's the famous PROMINENT trial. High risk diabetes, high triglycerides, fibrates. Very successful, 84 milligram per deciliter reduction. LDL increases and ApoB stays the same. What you see on the right is what you're doing. You're shifting larger particles to smaller ApoB particles, so you are not moving the needle on the total particle number.

Indeed, the decrease in triglycerides associated by a decrease in remnant cholesterol is compensated by the increase in LDL and ApoB. Not quite surprising, the impact on cardiovascular disease was actually nothing, identical. Fibrate does not remove the particles and it will not protect against cardiovascular disease.

What about the icosapent ethyl, the purified EPA. What we see there, there was a massive reduction of more than 25% in MACE, but the triglyceride reduction was only 32 milligram per deciliter.

Compare this to the more than 84 milligram in the fibrate studies. Interestingly, if you look at the low TG, mid TG and high TG, the icosapent ethyl was equally effective in normal and hypertriglyceridemia patients, so a massive benefit. The question remains, what explains this? Is this related to triglyceride reduction, which is minute or are there other effects? We hear that by other speakers will address that. So fun to be critical, but actually will we have a beneficial effect?

Here we are going to see that new agents do have the impact. This is the GalNAc-ApoCIII. You see that not only triglyceride is reduced by 70% but also LDL is reduced and ApoB containing particle number is reduced. Here we can actually test the concept whether triglyceride-rich lipoprotein reduction will reduce risk. On the right, the same for the ANGPTL3 siRNA data, also showing a reduction in particle number.

In summary, triglyceride reduction should not be used as a target in cardiovascular risk reduction. It's a mixed bag. Triglyceride-rich lipoprotein reduction, so both high ApoB and high triglycerides are for now the best surrogate for cardiovascular risk reduction. This remains to be established by potent compounds, who reduce both triglyceride-rich lipoprotein number, and triglyceride levels. I hope this explains why there's work to be done on the so-called triglyceride story.

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