Dear colleagues,

My name is Alberto Zambon from the Department of Medicine University of Padova and it will be a privilege in the next 10 minutes to provide you with a few considerations about residual cardiovascular risk in patients on statin therapy.

This is my disclosure slide.

Residual cardiovascular risk is the risk of macro-vascular events, including risk from established and emerging risk factors that we see in our patients in spite of current evidence-based medical care.

Now, the LDL-cholesterol is and remains the number one lipid parameter for screening, diagnosis and specifically managing cardiovascular risk in dyslipidemia. Now on intensive LDL lowering therapy, the residual risk of cardiovascular events can be accounted for by persistence or sub optimal control of some of the components of the atherothrombotic risk. We will focus today on excess LDL-cholesterol and triglyceride-rich lipoproteins. But let's keep in mind that inflammation, prothrombotic states and other lipids like elevated Lp(a) do contribute to the residual cardiovascular risk.

Now, we've come a long way with the starting from the mid-90s with the 4S trial, simvastatin, using intensification of statin therapy, high-intensity statin in TNT, LDL cholesterol 1.8 mmol/L or 70 mg/dL. We moved on more recently on the IMPROVE-IT trial of simvastatin + ezetimibe, reaching 1.4 mmol/L or 54 mg/dL. Last but not least with the introduction PCSK9 inhibition we were able to reach unprecedented low levels of LDL cholesterol, 30 mg/dL, 1.4 mmol or less. Now, facing this amazing capability of decreasing LDL cholesterol up to 85%, we are still facing a clinically relevant number of cardiovascular events, so called residual risk.

So we are focusing on what we need to do to decrease that number of events we clearly see on every day of clinical practice.

A piece of information comes from the very same trial I mentioned last FOURIER with Evolocumab, focus our attention on the left hand side panel; patients with diabetes, a population particularly at cardiovascular residual risk as compared to the population in FOURIER without diabetes on the right hand side. These are patients with cardiovascular disease, secondary prevention and as you can notice despite a significant decrease in cardiovascular events over 36 months in those on evolocumab and high intensity statin versus placebo. LDL cholesterol; 30 mg/dL in those on evolocumab. The number of events were still higher than those without diabetes on placebo which means high intensity statin and an LDL cholesterol of 90 mg/dL. So patients with diabetes despite wiping out LDL cholesterol, do remain at significant residual cardiovascular risk, as compared, for example, with the same patients, similarly recruited, without diabetes.

Now, we need to focus on all the atherogenic lipoproteins. We know that LDL, have been studied for decades, are a number one target, but in the past 10 years clear information came out about the atherogenicity of triglyceride rich lipoproteins, particularly in conditions such as visceral obesity, type 2 diabetes, chronic kidney disease.

Now, we consider for too long triglyceride-rich lipoproteins as innocent bystanders not related to the atherogenic process. What we know now is that they're highly atherogenic.

And we knew that from 1994. This is a paper from the R.J. Havel and J.P. Kane. They look at patients undergoing coronary artery bypass grafts and what you see on the top, are pictures of lipoprotein circulating in blood of one such a patient. On the right hand side the LDL, on the left hand side triglyceride-rich lipoproteins. Now, they took away the plaques from this subject and to their surprise, bottom right, they found of course, the LDL particles inside the coronary plaques, but up to 36% of the cholesterol in the coronary plaques of these subjects was coming from triglyceride-rich lipoproteins. So, triglyceride-rich lipoproteins are inside the plaque where they do cause the damage and this is 28 years ago. We simply forgot it.

Now, triglyceride-rich lipoprotein can be atherogenic as the LDL, by crossing the endothelial barrier, reaching the intima, being taken up by macrophages and leading to foam cell formation and plaque growth. They also can be atherogenic in a more sophisticated way. Thanks to the lipolytic products that are released in the blood due to the lipoprotein lipase action. They work as pro inflammatory agents, resulting in endothelial dysfunction. They also modulate the platelet activation and aggregation, promoting platelet aggregation and causing a prothrombotic state.

Now, that the LDL particles are pro-inflammatory, we knew it. This is a large study: 48,000 patients from the Copenhagen general population study. They look at a high sensitivity CRP per milligram or 1 mmol increase in LDL-cholesterol. The analysis was adjusted by a number of confounding variables, as you can see here listed here, every millimol or every 40 mg of increasing LDL cholesterol, CRP high sensitivity, CRP increase by 6%. Now, they look at the very same increasing the triglyceride rich lipoprotein cholesterol 40 mg, 1 millimol, and to their surprise they found that the high sensitivity CRP per mmol per 40 mg of cholesterol and triglycerides rich lipoprotein increased by 36%, confirming the pro-inflammatory role of these lipoproteins.

So, there is no surprise that Peter Libby recently, listing the non-traditional risk factors driving arterial inflammation, suggested that triglyceride rich lipoproteins are part of the family that sets the atheroma aflame.

Let's move to clinical evidence, this is coming from a larger retrospective cohort analysis from the Italian population. 158,000 individuals divided into tertiles, according to their normal triglyceride level less than 150, high triglyceride 150-500 or very high above 500. They looked at the other sclerotic cardiovascular event, the top part of the table, overall mortality, the bottom part of the table, multivariate analysis. Now, they looked at the risk of atherosclerotic cardiovascular events in this population, low intermediate cardiovascular risk as compared to the normal triglyceride population, the reference population, age and sex adjusted the hazard ratio gave a 20, a more than doubling actually of the risk of atherosclerotic cardivascular events, a 61% increase in the hazard ratio, when the multivariate analysis was adjusted for all the components you see on the bottom left of the slide. Overall mortality in a high triglyceride population as compared to normal triglyceride, increased by 61% in age and sex adjusted the analysis about 50% in the multivariate analysis. So increased moderate to severe elevation of triglyceride is significantly associated with increased risk of all-cause mortality and atherosclerotic cardiovascular disease.

Now, let's move to another country in Europe, France. This is the French Fast-MI registry, slightly less than 9,500 patients were recruited immediately after an acute coronary syndrome, established myocardial infarction. They looked at the REDUCE-IT criteria. So, out of 3789 patients who had a full lipid profile, they were able to select 472 patients, 12% of the population in the Fast-MI registry who fulfilled the criteria of the REDUCE-IT trial. Basically, age over 55, hypertriglyceridemia, well-controlled LDL. As in the REDUCE-IT trial, this population the Fast-MI registry was at a high risk of cardiovascular disease. On the left hand side of the table, 36.7, exactly overlapping the established cardiovascular disease, the risk of cardiovascular events in the REDUCE-IT, and the other point is that the risk in the Fast-MI REDUCE-IT like population was much higher than a population of the patients in the very same registry, but not fulfilling the hypertriglyceridemia criteria that REDUCE-IT had.

Last study, coming from Copenhagen General Population. 13.000 patients looking at ApoB and particularly focusing on known HDL-cholesterol LDL cholesterol above or below the median. Reference populations are patients with the LDL cholesterol and known HDL cholesterol below the median. Now, as you can see those at a higher risk, top panel, all-cause mortality, bottom panel, myocardial infarction, are those that had an LDL cholesterol well controlled, and you see the values in the bottom part of the slides, but known HDL cholesterol was not below the medium, it was above the medium. Now what it means, it's clearly highlighted on the left hand part of the slides, If you have an LDL well controlled and known HDL is not well controlled, clearly the culprit are triglyceride-rich lipoprotein. Once again, hypertriglyceridemia, in the context of well-controlled LDL, show an increased 23%, increased risk of all-cause mortality and 82% of myocardial infarction.

In the conclusions, ladies and gentlemen, raised triglyceride concentrations are an additional riskfactor for cardiovascular disease and all-cause mortality. They are associated with inflammatory components of the atherosclerotic plaque, leading to a phenotype typical of the unstable plaque. When you look at three European countries, in the French Fast-MI registry, cardiovascular risk related to elevated triglycerides, the REDUCE-IT like population, about 12% of the population in the registry, was associated with an elevated risk of cardiovascular events similar to what has been seen in the REDUCE-IT trial. In the Italian population, elevated triglycerides were associated with higher cardiovascular events and overall mortality. And finally, in a large statin-treated cohort from the Copenhagen study, elevated triglycerides lipoproteins was associated with higher all-cause mortality, 23%, and MI 82%.

So just to bring it to the conclusion: When we talk about cardiovascular residual risk in 2022, we should be aware that the optimal control in terms of reducing risk of cardiovascular events in residual risk, should take into account a nice control of LDL cholesterol and well controlled triglyceride-rich lipoprotein levels.This is a key step for effectively managing the risk of cardiovascular events.

Thank you very much for your attention.

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