I am going to talk about how you integrate icosapent ethyl in your day-to-day clinical practice and how you can use this to reduce cardiovascular risk. These are my disclosures.

When we talk about cardiovascular risk reduction, there are so many different aspects. That includes reduction of atherogenic lipoproteins, reducing inflammation, improving metabolism, and of course, improving the coagulation parameters. When you think about a molecule like icosapent ethyl, which is very pleiotropic, it's really acting on multiple different targets and not just one. For instance, it's acting on the lipoproteins by reducing triglycerides. It's acting on inflammation, and it's also acting on the platelets and the coagulation pathway.

Why do we need to think about adding icosapent ethyl to statin therapies and other LDL therapies? It's because we know from landmark clinical trials like IMPROVE-IT that reducing LDL alone does not decrease cardiovascular events. We saw, in IMPROVE-IT, even when we got the LDL to phenomenally low levels, for instance, here, 53, there was still an unacceptably high cardiovascular event rate. That's because of other factors including triglycerides, non-HDL, and hyperglycemia. We also need to remember that cardiovascular risk reduction is not black or white. There are a lot of gray areas. That gray area are these high-risk primary prevention patients. These are the patients that have high-risk features such as diabetes, elevated levels of inflammatory biomarkers, but yet they haven't had an event. Sometimes they're often missed in clinical practice as not having high risk. This is where we need to do a better job in risk-stratifying these patients.

Many of these patients were enrolled in the REDUCE-IT trial. We have data that a compound like icosapent ethyl can be very beneficial for these patients. Another disease that we need to think about when we think about risk reduction is type 2 diabetes. It is a cardiovascular disease, and there are so many underlying mechanisms in type 2 diabetes that really contribute to increased risk, including elevated triglycerides, increased inflammation. We need to think about these patients with type 2 diabetes as high-risk primary prevention patients.

When we talk about triglycerides, you can't look at triglycerides in isolation. They are really a reflection of the bad company that they keep, such as atherogenic lipids, ApoB, increased levels of inflammation. You really need to be thinking about triglycerides in the global spectrum of all of the other compounds and proteins that are flowing with them. You've already heard how elevated triglycerides are a marker of increased risk, but the elevation in risk doesn't start when the triglycerides go over 150. It actually starts much more at levels we would consider normal, such as triglycerides over 100. That's where you see the steepest increase in the curve. You can't just start thinking about triglycerides when they're over 150. You need to be thinking about when they're over 100. We saw in the REDUCE-IT trial that even if triglycerides were less than 150, there was still benefit from icosapent ethyl, and that speaks to that icosapent ethyl goes beyond just triglyceride lowering. When we look at what icosapent ethyl does, it really impacts multiple components of residual risk. That includes the proatherothrombotic phenotype, that includes the patient that has subclinical elevation of high sensitivity CRP, and the patient with elevated triglycerides. That's your typical metabolic syndrome patient. It's also your patient with type 2 diabetes.

When we think about icosapent ethyl, we really need to be thinking about it as a compound that addresses multiple aspects of residual risk, including the elevated triglycerides, including the proatherogenic phenotype, and the subclinical inflammation. What we saw in REDUCE-IT, it wasn't just triglycerides that were lowered, we also saw a decrease in ApoB and high-sensitivity CRP. ApoB is a very important molecule to pay attention to because it's really the backbone of all atherogenic lipids, including LDL, VLDL, and lipoprotein(a) When you have a reduction in ApoB, you're really having a reduction on atherogenic lipoproteins.

Now let's talk about how do we incorporate icosapent ethyl into our day-to-day clinical decision-making. It's nice to see that the 2023 AHA/ACC guidelines have really incorporated this into patients who have chronic coronary disease. What they emphasize is high-intensity statin first, LDL lowering is paramount, and we have to maximize the statin. After we do that, we can consider adding icosapent ethyl, both for our very high-risk patients and those patients that are not at very high risk.

Now, let's look at a patient, a real patient of mine, and apply some of what we've learned into the clinical management of this patient. We have a 66-year-old woman who has a history of coronary artery disease. She had an acute coronary syndrome event and PCI of the LAD recently. She also has hypertension, Type 2 diabetes, atrial fibrillation, and hypothyroidism. Her current medication regimen consists of a statin, atorvastatin 40 milligrams, blood pressure medication, amlodipine. She's on aspirin and clopidogrel since she recently had a stent. She's on levothyroxine. She's on apixaban for her atrial fibrillation, and for her diabetes, she's on metformin and an SGLT2 inhibitor empagliflozin. Her blood pressure is 130/85 and her BMI is elevated at 30, and so let's review her laboratory data. Her total cholesterol is 140. Her HDL is 30 and her calculated LDL is 53. Triglycerides are elevated at 287. Her non-HDL is 110. Her hemoglobin A1C is 7.6, and her creatinine is slightly elevated at 1.4 with a slight reduction in eGFR of 55. When you look at her lipids, you might think her LDL is great at 53, but you have to remember that when someone has elevated triglycerides, it leads to a falsely low-calculated LDL. This is where you need to look at the non-HDL. Typically, the LDL and the non-HDL should be about 30 points within each other. If you have an LDL of 70, the non-HDL should be 100. You see here that there's a discordance between the LDL and the non-HDL with the non-HDL being higher You really need to focus on the non-HDL. The reason that there's a discordance is because of the elevated triglycerides. With this patient, you do want to focus on LDL lowering, but in addition, you want to optimize lifestyle strategies because lifestyle strategies are very synergistic with the pharmacotherapy. With this patient, you really want to drive her true LDL to less than 55. Here's where you might consider getting a direct LDL or looking at other biomarkers such as LDL particle number or ApoB because her LDL is falsely low. You want to optimize statin therapy, and you can also use non-statin agents such as ezetimibe to get your LDL levels as low as you can go. This is also a patient that has a lot of other comorbidities such as type 2 diabetes. She's obese with an elevated BMI. All of these other factors are also contributing to increased risk. You want to add an agent like icosapent ethyl that's not only going to address her triglycerides, but it's going to have an impact on global residual risk.

In summary, triglycerides are a marker for elevated cardiovascular risk, even with mild elevation greater than 100. In clinical trials where we see pure triglyceride lowering, we don't see cardiovascular benefit. When we see triglyceride lowering along with lowering of ApoB, such as what we saw in REDUCE-IT, we see improvement in cardiovascular outcomes. When you think about a compound like icosapent ethyl, you don't want to pigeonhole this compound as just a compound for triglyceride lowering. It really should be considered as an agent for global CV risk reduction.

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