Triglyceride-rich lipoproteins and residual CV risk

Ladies and gentlemen, thank you very much for allowing me to share some data on the role of triglyceride-rich lipoproteins in cardiovascular disease. These are my disclosures. So, the question is, after the successes we’ve seen in LDL lowering and lowering inflammation, is it still relevant to actually discuss triglycerides or is merely an epiphenomenon? Well, let’s go back to the facts. The prevalence of high triglycerides is massive. It’s between 15 to 40-percent of the population where you may actually encounter hypertriglyceridemia. And this is expected to increase in view of the massive epidemic of overweight and obesity in diabetes. The residual cardiovascular risk in high-risk patients, even in contemporaneous trials where we claim to have established cardiovascular risk management adequately, is still very high, between 1.5 to up to 5-percent MACE recurrence per year. And if we look at the current cardiovascular medication, the impact of those medication on triglycerides is actually meager. In statins, it’s maybe 10, 15-percent. PCSK9, maybe up to 20-percent. But that’s also at current. Triglyceride-rich lipoproteins are not really addressed by this medication. So, let’s go to clinical practice. Here you see a very frequent patient, 55 years old, type 2 diabetes, hypertension, overweight, well controlled with respect to the LDL. But if you look to the non-HDL and the triglycerides, it’s apparent that there’s a lot of recurrent atherogenic lipid burden in these particles. So, what should be the next step in this particular patient? Well, let’s zoom into the content of these particles. Here, you can actually see the entire specter of the cholesterol particles. These are the Apo(b)-containing lipoproteins. So, basically, all that’s atherogenic. You can see that the traditional hypertriglyceridemia is caused by VLDL1 and VLDL2 but then there’s the IDL, intermediate density lipoproteins, and there’s the LDL cholesterol. And I will not address the Lp(a), which is also present in the Apo(b)-containing fraction. And here you can see that the triglyceride-rich lipoproteins are actually the combination of VLDL1, VLDL2 and IDL. Now, this also shows that if you only measure LDL, you actually do not take into account a very substantial part of the atherogenic lipoproteins, being the IDL and the VLDL particles as well as the chylomicron remnants, which are also known to have the capacity to end up in the subendothelial space and contribute to the accumulation. So, why are these particles so atherogenic? Well, if we compare the traditional LDL particle with the VLDL/IDL particles, you can see that 30-percent of total cholesterol burden in the Apo(b) fraction is actually not in the LDL but in the triglyceride-rich lipoproteins. So, basically, triglycerides equal a hidden burden of cholesterol, atherogenic cholesterol but this time in the triglyceride-rich fraction. And what we know is that there’s a four-fold higher cholesterol content in one triglyceride particle as opposed to the LDL particle. In addition, the triglyceride-rich Apo(b) lipoproteins are enriched in apolipoprotein E and other factors which result in accumulation and sticking of these particles in the subendothelial space and triglycerides are known to be associated with systemic inflammation, whereas LDL is not. So, there’s a good pathophysiological rationale why triglycerides are atherogenic. So, is there sufficient evidence? If we look at epidemiological surveys, yes. Hypertriglyceridemia, both fasting and nonfasting, is associated here in the metanalyses of a hazard ratio of 1.7. And we also know that if we go to the higher values of triglycerides, the increase is particularly present if triglyceride absolute values are high. Look in these data from the Copenhagen Heart Study. If you have hypertriglyceridemia higher than 5, look at the enormous increase, up to fivefold compared to those with normotriglyceridemia. So, high triglycerides, high remnant cholesterol hidden in triglycerides is associated with a substantial residual cardiovascular burden. Is this causal? Well, I won’t go into detail but the Mendelian randomization studies of various groups have simultaneously shown that if we look at the genetic abnormalities, genetic variance which are associated with causing high triglyceride levels there’s a clear increase in the risk. And this actually has a very strong implication that hypertriglyceridemia is causally related to cardiovascular disease and events. I think the nicest analysis has been published by Brian Faranz [ph] and colleagues where he actually looked at genetic variance for the LDL cholesterol. Here, you can recognize PCSK9, Apo(b), etcetera, and in blue you can recognize the variance, which are only associated with hypertriglyceridemia. Now, on the X axis, you can see the absolute lower of plasma Apo(b) caused genetically. On the Y axis, you can see the risk change. Now, it’s apparent that it’s all on the same line. So, these data actually imply that it doesn’t really matter whether we call it LDL or triglyceride-rich lipoprotein. Whenever there’s an Apo(b) particle containing cholesterol, that is what conveys the risk. So, we have to look at triglyceride because of the hidden LDL cholesterol which is validated by this statistical subanalysis. Then it’s always been a question, if we already treat with statins, is triglyceride still relevant? Well, post talk analyses have shown that also in statin treated subjects, residual triglyceride load is still associated with risk. And actually, you can make a very good estimate what 1 mmol triglyceride reduction versus 1 mmol LDL reduction, how it will translate into cardiovascular risk change. So, do we have drugs which efficiently lower triglycerides? Well, as I already said, statins have an impact but not so strong. Fibrates have an impact. Fish oils have an impact and emerging drugs have very strong effect on hypertriglyceridemia. I will skip the fibrates because we all know what happened to the fibrates, not effective in the whole group but clearly effective if you look solely at hypertriglyceridemia high-risk patients at baseline. Let me briefly say a few things on the fish oils. We have known the STRENGTH Study with the EPA/DHA combination versus the icosapent ethyl and REDUCE-IT Study which is solely EPA. We’ve seen that in the REDUCE-IT Study, 4 gm of fish oil were not so effective on triglyceride lowering. They were somewhat effective on CRP reduction but they were massively effective in reducing cardiovascular event rate. Now, surprisingly, in the STRENGTH Trial, the combination of DHA and EPA had the same effect on triglycerides but there was no effect on cardiovascular outcome. Now, what could explain this? Well, the first thing that’s clear is the placebo was really different. That might have contributed a little bit to the extreme positive effect of EPA but not the total effect. And I think the major difference here is that REDUCE-IT, the very positive result, may have been the result of a very significant increase in the EPA going from 26 at baseline to 144 mcg/mL after treatment as opposed in the STRENGTH where the lift was from 21 to 90 mcg/mL. These data imply that there’s some kind of a threshold for EPA plasma levels in order to convey the benefit. And actually, this implies that the benefit of the high-dose EPA is not due or for a minor part due to lowering of triglycerides and may establish one of the other effects of the fish oils. So, our enthusiasm is that now that we have resolved LDL with very effective interventions, we can tackle Lp(a) cholesterol and triglyceride lowering if we look at the near future, there are various interventions who have a very promising effect, both on triglycerides and LDL and we hope that these combined interventions will also reduce the last remaining atherogenic lipid fraction, so, the triglyceride-rich lipoproteins, which eventually will virtually abolish the contribution of residual lipids to the cardiovascular risk. So, in conclusion, triglyceride-rich lipoproteins is more atherogenic than LDL cholesterol. Triglyceride-rich lipoproteins cause atherosclerosis as demonstrated by the genetic data. And triglyceride-rich lipoprotein reduction is highly likely to reduce cardiovascular disease risk as long as it coincides with a significant Apo(b) reduction based on the genetic data and it will always be second-line therapy after maximal lowering of the LDL/Apo(b) fraction. Thank you for your attention.