Well, thank you, Martha. So first of all, isn't it great to be at a live meeting? So we got beautiful weather outdoors. It's so much fun to see friends that I haven't seen in a long time, and it's nice to be thankful that things are getting better. All right, these are my disclosures. So certainly statins are our foundational therapy, but it doesn't mean that that's the only therapy, and it's very important, and when we treat one patient at a time, we manage to optimize that person's LDL and other risk factors. So we've got established nonstatins that can be used alone or in load with statins for lowering LDL cholesterol, PCSK9A with HERV inhibitors, I put at the top because they give the most LDL reduction, 60%, plus a statin, you can be getting 75% from baseline, almost 80%. Even low-dose statins plus a Zetimibe can be giving you 40 to 50%. Very high-efficacy statins plus a Zetimibe can be giving you 60 to 70%. Now resins and niacin, we do not have the data with it. Resins have not been studied in outcome trials with statins. Niacin has two negative trials, so they are further down the list, particularly niacin. So there was a very exciting time when the statin trials first came out. In 2013, there was a set of guidelines by the ACC that focused on the intensity of statins, and there was a lot of concern at that time that perhaps statins did something more than lower LDL cholesterol, and we know that there are pleiotropic effects, such as a CRP reduction. However, what's come out is after those set of guidelines, and we heard about all these other trials, but you had the IMPROVE-IT study, then Fourier, SPIRE 1 and SPIRE 2 might remind people that Pfizer had a program on the focusizumab. These trials were stopped early. Despite stopping early, they lowered cardiovascular events over a short duration of therapy. So that's another large piece of data there. The REVEAL study used anacetrapib, a CTP inhibitor that lowered LDL cholesterol, even though the trial was designed to include patients with fairly low LDLs to begin with, still showed events, and in the longer duration of follow-up, showed further event reduction, and in ODYSSEY outcome 6 trials, 122,000 patients, all showing benefits of non-statin therapy with further LDL reductions providing further event reduction. Now the first of these was the IMPROVE-IT study. This trial was an unusual design. It was ACS patients, and I say unusual, the control group had an LDL of 70. The treated patients, 54. So it's a very small increment in LDL cholesterol, and it led to a small increment in relative risk reduction of about 6.5%, statistically significant. Now what was interesting, this study had some problems with adherence. It was a long trial, and there were a lot of things that were said that were somewhat negative about ezetimibe that reduced enthusiasm during the study. But what is fascinating is if we look at which patients had the greatest benefit. And this was a clinical risk score, TIMI risk score, but if you had any of these other factors, if you had three or more of their factors, such as hypertension, age, diabetes, prior stroke, notice that the placebo group had a 40.2% event rate. The treated patients, 33.9. So it's an 8.3% absolute risk reduction. You treat 12 patients to reduce an event. So that's really quite impressive. This was also done by biomarkers. So not clinical criteria, using biomarkers, same type of thing, the high-risk people had the greatest benefit. We're going to come back to that theme. Now the PCSK9 inhibitors that we have, two approved ones. The first trial published was the FOURIER study with EVA-LOCOMAB. They took high-risk individuals. They had to have an LDL over 70, greater than or equal to 70, or non-HDL greater than or equal to 100. So this was kind of a concept of a threshold. On a statin, LDL still having elevated levels or non-HDL cholesterol, which is actually a better marker for risk than LDL cholesterol, randomized to EVA-LOCOMAB or placebo. Similar design, different patient population with ALI-LOCOMAB, but a placebo-controlled trial post-ACS, slightly more complicated design. They began with 75, titrated to 150, and the goal was to have LDLs 25 to 50. They even stopped the drug if the LDLs went too low. But what ends up happening, both studies showed event reduction. Now there's a very important caveat that Martha mentioned earlier. It's not just the amount of LDL reduction, it's the duration of therapy. And this was one of the things that was unfortunate about these studies. In the hurry to generate data in FOURIER, they actually expanded the sample size from 18,000 to 27,000. It was an event-driven trial. Now that will give you events sooner, but you end up with a shorter duration of therapy, 2.2 years. The duration of therapy in the statin trials was usually around 5 years. So this, if you notice the curve is coming apart by landmark analysis, there was greater reduction in the second year than there was in the first year. Odyssey outcomes was a little longer, but only 2.8 years. So these trials were shorter. They both reduced events. They were highly significant in terms of the benefit. What was very interesting, getting LDLs to levels which we had never achieved before, there was no increase in adverse effects. If you got LDLs down and looking here, you get LDLs less than 40 down to 10, 20, there was no increase in adverse effects seen in the FOURIER study. Remember our clinical trials are done with the time to first event analysis. When you're treating patients, and if you are a patient, you're not just concerned about the time to the first event. You don't want to have the second or third event, right? And our patients don't want to have that. So what ends up happening is you underestimate the benefit. And this was Odyssey outcomes. There were 191 events prevented. There were 385 total events. So you're only getting about half of that if you're looking at just time to first event. And if the studies had been longer, it would have been even larger in terms of second and third events. Excuse me, the colors got messed up here, so those are not correct in terms of the coding of the type of event with the colors. All right, now, I do better remembering concepts than memorizing tables. And so, to me, the concept that's been there for all the guidelines is the greater the risk of the individual, the more aggressive we need to be in regards to treating lipids and other risk factors. That's an easy concept. So for ASEVD, what drives events? The burden of atherosclerosis. And what did these studies all show by various analyses? The more that you had, the greater the event rate and the greater the benefit. Prevestal coronary disease, peripheral arterial disease, carotid disease, multibed athero, diabetes, we know it's more diffused, age, and activity of atherosclerosis, recent ACS. Diabetes is both the burden and the activity. High CRPs, very high LDL, non-HDL, and elevated levels of lipoprotein A. These people all showed greater risk and greater benefits of treatment. Now our guidelines have gone, we've changed, and now it's not just secondary prevention, but it's also, we know there are some people who are more stable, some people who are very high risk. This is one way of remembering that is there is a table, and I think it's a very clear table about these types of clinical parameters. Over half of your patients are going to be in the very high risk category. So to summarize the key points, lower LDL levels and longer duration of therapy are better for CD outcomes. Reduction in the first event does not reflect the full benefit of total event reduction for the patients. Very high risk patients, recent MI, multibed coronary disease, PAD, other characteristics would define very high risk patients. These individuals have the greatest benefit because they have the greatest risk from intensive lowering of LDL. So if you look at the absolute risk in the absolute LDL reduction, you can use that to predict the absolute benefit of therapy. We did not see any safety signals for PCS cannabinoid inhibitors, Zetamib has also been an extremely safe agent for PCS cannabinoid inhibitors other than the injection site reactions. Thank you very much. Thank you.

therapies

lowering LDL cholesterol

statins

non-statins

PCSK9 inhibitors