I'm Dr. Lawrence Leiter. I'm an endocrinologist and professor of medicine and nutritional sciences at the University of Toronto It's my pleasure to present you a clinical case on tackling risk reduction in patients with atherosclerotic cardiovascular disease. Here are my disclosures.

Let's start with this case. The case is that of Maria, a 68-year-old retiree. She is an ex-smoker. She is overweight. Her BMI is 28.8. Blood pressure elevated at 138/98. She has a 15-year history of hypertension. She had a STEMI, an ST-elevation myocardial infarct about two years ago, followed by a PCI with LAD stenting. She is on atorvastatin 40 mg. She is on low-dose aspirin. She is on valsartan 160 mg daily. She is also taking some fish oil capsules. Bottomline, she is a high-risk individual with established cardiovascular disease.

Here you see her laboratory values, and nothing here really jumps out at you. Her total cholesterol is 3.9 mmol/L, her LDL 2.0, HDL 0.9, triglycerides 2.2. Her non-HDL is 3.0. Her eGFR in the normal range at 67. Her hemoglobin A1c 6.0%, so just at the bottomline of the pre-diabetes. Is Maria at increased risk for future cardiovascular events? Hopefully, you will all say yes.

Which of her factors are contributing to her persistent CV risk? Really, if you look at potential risk factors, she has got virtually all of them despite the fact that her lipid values don't jump out at you.

In fact, if we look at the various statin trials, statin versus placebo, even in the statin-treated group shown in orange, although their risk of an event is reduced, they're still having a lot of events. Even if you look at the more recently completed trials with PCSK9 inhibitors, where patients are achieving very low LDL cholesterol levels, there is still a lot of events occurring in the treated patients.

LDL treatment, of course, is important, but there are many other factors beyond LDL cholesterol that may also play a role in the pathogenesis of cardiovascular disease and contribute to CV risk, including triglycerides.

There are a number of epidemiologic studies. Here you see the two Copenhagen studies, the Copenhagen City Heart Study and the Copenhagen General Population Study. If you look at myocardial infarction, ischemic heart disease, all-cause mortality, or ischemic stroke, the higher the triglycerides, the greater the risk. Notice, you don't have to have very high triglycerides to have an increased risk. Even in the 2 to 3 mmol/L range, the risk is already increased.

Furthermore, even in statin-treated patients, if you look at the PROVE-IT TIMI 22 study, even in those patients who had an LDL at goal with statin monotherapy, those patients who had a triglyceride level above 1.7 mmol/L had a 43% higher risk of having a coronary event than those patients who had a triglycerides under 1.7.

Well, if triglycerides are a risk factor, what evidence do we have that lowering triglycerides reduces risk? Well, if you look at the various fibrate trials, including the PROMINENT study with pemafibrate that just came out, trials with niacin, trials with mixtures of omega-3 fatty acids, none of them reduce the primary MACE endpoint.

Exception being, of course, the REDUCE-IT trial, and just very, very quickly, REDUCE-IT included patients with established CVD or diabetes plus one risk factor who had an LDL relatively optimized on statin therapy and mild to moderate hypertriglyceridemia randomly assigned to the addition of icosapent ethyl (IPE) versus placebo, and landed up being followed for an average of about five years.

The primary composite endpoint shown on the left, a MACE-plus endpoint, 25% relative risk reduction, an absolute risk reduction of 4.8%, giving an NNT of just 21. For the key secondary composite endpoint, the more traditional MACE, 26% relative risk reduction, 3.6% absolute risk reduction, giving an NNT of 28.

Let's come back to Maria. Her triglycerides were 2.2 mmol/L, so do her triglyceride levels fall within the triglyceride range that confers CV risk? Absolutely.

Let's come back to her. Again, she has multiple risk factors, and as a clinician, the challenge is, which are the risk factors do we go after? and which will the patients accept? We're living in an era of polypharmacy. We have multiple positive outcome trials for risk prediction, yet our patients are often pushing back. They don't want to be on a lot of medications. We have to negotiate with our patients what to go after.

What's happened here is she has agreed as a first step. She said she is already on LDL-lowering therapy. She is already on anti-hypertensive, so she wants to optimize those before she'll consider another risk factor.

What's done, her atorvastatin is increased to 80 mg, ezetimibe 10 mg daily is added, as is amlodipine 5 mg daily for her blood pressure. She is advised to stop her over-the-counter fish oil capsules because they've never been shown to have any cardiovascular benefit. She comes back, but I don't wait a long time. She comes back one to two months later. She is better with her diet. She has lost 4 kilograms. Her blood pressure is improved. Her lipid profile is generally improved as well. Her LDL is down to 1.3. Her triglycerides are 1.9. Again, don't jump out at her, but she still falls into the inclusion criteria of the REDUCE-IT trial, so therefore, would you add icosapent ethyl 2 grams bid?

Hopefully, you will all say yes.

If we look at what the guidelines say, we recently published a review of major medical society guidelines and statements from around the world.

Remarkably, over the last four years, 32 different global medical societies recognize IPE as an important treatment for ASCVD. These are guidelines in the United States, in Canada, and in Europe.

She has IPE 2 grams bid added to her other therapies. She comes back another month or two later. Her LDL continues to be 1.3. Her triglycerides are a little bit better at 1.5, but this is really irrelevant because what the REDUCE-IT trial showed of course is that the benefit observed was not related to triglyceride lowering. It was similar if patients had higher or lower triglycerides at baseline, higher or lower on-treatment triglycerides.

Before I conclude, just a moment to talk about shared decision-making for CV reduction. It's important that we not just have the evidence, but we have to understand our patient's perception of risk, and explore their preferences and priorities. We have to consider the patient's unique needs, situation, and CV risk, alongside trial data and guidelines. We have to effectively communicate risks versus benefits. We have to discuss available options, alternatives, and avoid information overload. Finally, we need to have shared decision-making in order to optimize medication adherence and response, and we need to readdress the approach and goals as necessary.

In summary, what did this case teach us? Well, we know that many individuals with even significantly reduced LDL cholesterol levels are still at increased cardiovascular risk. IPE, icosapent ethyl 4 grams daily lowered CV events in statin-treated patients, and offer a novel add-on lipid-lowering option in appropriate patients. Importantly, the REDUCE-IT results cannot be generalized to other fish oil preparations. Finally, we must effectively share decision-making with our patients in order to enhance uptake and persistence with evidence-based therapies. Thank you.

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