statin therapy, which is really the backbone of lipid management these days. We talked about why patients may not be able to get to goals while using statin therapy. And then we started to talk about two non-statins for which we have the outcome stata, that is ezetimibe and PCSK9 inhibitors. And now we have two more non-statins approved. We heard about one of them in Clisteran, which is the siRNA. And now I'm gonna talk about the next non-statin, which was also approved by the FDA, and that is bampidoic acid. These are my sources of research support and other disclosures. So this is really what I want to talk about. I'm gonna build on what was already discussed by Dr. Gulati, Dr. Palantine, in terms of challenges with statin therapy. There are some challenges that we all face as clinicians, as well as our patients also face related to statin therapy. So what are some of those? Some have been highlighted. I'm gonna just build on those a little bit more. Then the question is, where could bampidoic acid fill that gap? But do remember that holds true for any non-statin therapy, whether that's ezetimibe, whether that's PCSK9 inhibitors, whether that's in Clisteran. It's the same gap that these non-statin therapies are going to fill in, where statins may not be able to get us to where we want ourselves in terms of our patients to get to. And then I'm gonna talk very quickly about the mechanism of action, efficacy and safety of bampidoic acid, what we need to know as clinicians, and then I'll summarize that. So that's really what we'll talk about. Now we talked about use of statin therapy. I remember when I was a medical resident, prove it was a trial that came out that really we went line by line. This was one of the most important trials in our journal club as a medicine resident, where moderate intensity statin therapy, i.e. Pravastatin was compared to 80 milligrams high-intensity statin therapy, where it showed that there was a reduction. I believe it was a good 20, 22% relative risk reduction by using a high-intensity statin therapy in patients after acute coronary syndromes. This was one of those studies that led to that less than 70 target back in those days. And everybody was very excited about it. Now when I look back at it, this is the data for those patients in a clinical trial setting. Remember, these are not our everyday patients. These are patients in the clinical trial, your most adherent patients, who were receiving 80 milligrams per tour by statin. So we're looking at the active treatment arm. And when you look at follow-up LDL cholesterol levels despite receiving high-intensity statin therapy in a clinical trial setting, and when you see what proportion of those patients have LDL cholesterol levels above 70, it's 55%. So if you're following the U.S. guideline in an ACS patient, you'll have 55% of the patients, if they were perfect patients, who will continue to have high LDL cholesterol levels. If you go by the European cutoffs of 55, I've drawn a line here at 50, it's about 75% of the patients who will continue to have high LDL cholesterol levels. So in real world, it may be even worse than what we're seeing here. This is data from the Sweetheart study. Very, very actively managed ACS patients. Perhaps this is one of the highest rates of high-intensity statin therapy that at least I have seen, 87%. In U.S., in the best-case scenario right now, the healthcare systems that do the best have about 50% of their patients in secondary prevention who are receiving high-intensity statin therapy. And statin use is somewhere between 80 to 90% in the best-case scenario. I think you saw some data from Gold Register, which was about 90%, and 50% were on high-intensity statin. This is much better than that. This is ACS patient. So that's 87% of the patients who were receiving a high-intensity statin therapy, but with that, only 17% had LDL cholesterol levels below 55, which is the European target, as you would know, in secondary prevention. If you increased high-intensity statin therapy to 100% use, which, again, is probably not possible, you will have about 21% of your patients who will get to LDL cholesterol levels below 55. Just gives you an idea as to how difficult it is with just statin therapy. If you were to use ezetimibe, right, in three-fourths of those patients, you will get another 28%. So you're close to 49, 50% of your patients will get to LDL cholesterol levels below 55. You will still be left with about 50% of your patients in whom you may end up using a PCSK9 inhibitor, i.e. another non-statin. So that is the challenge is that, it's one of the challenges that we face as clinicians, that it takes quite a bit of effort to drop these LDL cholesterol levels down. Of course, you have heard enough about statin-associated musculoskeletal side effects in registry data. It's somewhere between 5% to 20%. It can go up to 25% as well. And that is another reason, right, that we all have problems in terms of intensifying therapy on our patients, and one of the most common reasons after filling the prescription why patients stop statin therapy is statin-associated musculoskeletal symptoms or statin-associated side effects. So now, on that background, why do we need non-statins, right? One is aggressive lowering. The other is side effects from statin therapy that some patients may not be able to tolerate. Now, we can have a discussion on what causes those side effects, how real those are, and you saw some data from the SAMHSA trial, how much of that could be placebo effect versus the real effect from the medication itself. But the fact is, when you're seeing a patient, you're seeing a patient, right? They come to you with symptoms. Bampedoic acid, again, you have heard the PCSK9 inhibitors, mechanism of action, statins we all know, we talked about in Clisteran. Now, let's talk a little bit about bampedoic acid. So, bampedoic acid is a prodrug. It needs to be activated. Liver has this enzyme, what we call the ACSVL1. It's a very long-chain acyl-CoA synthetase, which is present only in the liver. And that is why this drug is only active in the liver. It is not active in the muscle. So that's why some people think that it may not cause as many musculoskeletal side effects as statin does. Now, that remains to be seen in larger trials as to whether that holds true or not. And then, its active metabolite inhibits an enzyme, which is ATP citrate lyase, ACL, which is in the same pathway as HMG-CoA reductase, two steps above that, in the same pathway that statins inhibit HMG-CoA reductase. So it's the same pathway, leads to lowering of the LDL cholesterol levels within the hepatocyte. So, hepatocyte takes up more LDL from the circulation, from plasma. And again, it leads to more LDL receptor upregulation. So the mechanism is in the same pathway. So just keep that in mind. Now, once it does its work, it undergoes gluconidation and then it's excreted by the kidney. And then, that is where I think there's one more part that is important, that it is excreted by this O2 receptor. This is the same receptor that is used to excrete uric acid out into the urine as well. That's why one of those side effects, it was one of the questions, hyperuricemia. It causes elevation of uric acid levels. So just remember that, that it's a prodrug that needs to be activated in the liver. That enzyme is not present in the muscles, so it stays in the liver. It's in the same pathway as statin therapy, which again, becomes important when you're using it with statin therapy. And then, the mechanism of why it may cause uric acid elevation. Now, genetics used to be that we would have drugs and then we would do genetics to see if those drugs would work. Now, the field has turned on its head with PCSK9 inhibitors. One of the most beautiful stories that I learned out of that was, we learned genetics first, then we developed a medication. In the same way, if you look at ATP citrate lies in terms of the Mendelian randomization studies, it would seem to be that we're on the right path. We do not have outcomes data with the ampidoic acid, but if we look at Mendelian randomization studies, the LDL cholesterol reduction you get because of ATP citrate lies-related polymorphisms are associated with improvement or lower risk of cardiovascular events. So, genetics might be supportive. Now, let's look at the clinical trial program for the ampidoic acid. These are all clear studies, right? So, it's Orion for all the influceron studies. It's clear for all the, and this is not the clear that some of you went through when you came for ACC meeting through TSA. It's a different kind of clear. So, here you have clear harmony, clear wisdom, clear serenity, and clear tranquility. That gave you some peace, I guess. But again, as like any other clinical trial program, you initially start out with your most high-risk patients, so those with ASCVD or heterozygous FH because that's where the most need is, and then you move slowly but surely towards more high-risk primary prevention patients. Clear harmony is the trial that had the most number of patients, and these are phase three efficacy programs, not effectiveness programs, which, of course, I'll talk about. So, these are some of the data on clear harmony. About 15 to 17% LDL cholesterol reduction, whether you look at intent-to-treat analyses or on-treatment analyses. So, about 16 to 18% LDL cholesterol reduction in this particular trial, which is clear harmony. When you look at adverse events, overall comparable, but adverse events leading to discontinuation were slightly higher in the bampydoic acid arm. Importantly, there was about a 0.7 to 0.8 milligram per deciliter increase in uric acid, which I think I went over as to what could be the mechanism explaining that, and symptomatic gout was about a percentage higher in those patients receiving bampydoic acid. So, that's something, as clinicians, we need to keep in mind if we are using this medication. The next thing that is important is, I showed you that pathway, that it's in the same pathway as statin therapy. So, if you are using it in patients who are already on statin therapy, then the efficacy is little lower compared to if the patient is not on statin therapy. And you see that here from the Clear Wisdom efficacy study-related data, that you can get up to a 25% LDL cholesterol reduction in patients who are not on any statin, versus if you look at those who are lower barbit or high intensity, you're looking more like 15% LDL cholesterol reduction. One last thing related to efficacy studies is that this medication has also been studied along with ezetimibe, which of course leads to a reduction of cholesterol absorption in the gut by inhibiting NP-C1L1 receptor. So, this has also been studied along with ezetimibe. So, when you use a combination of bampydoic acid with ezetimibe, you get about 35% LDL cholesterol reduction. So, you're more in that moderate intensity statin therapy kind of range for LDL cholesterol reduction. So, those were some things that we all need to know in terms of efficacy, some major side effects. Again, the other side effect that is still being really looked at, and I'm hoping that the large outcomes trial will provide us more information, is increased risk of tendon rupture or injury. It's about 0.5% with bampydoic acid. Again, rotator cuff, bicep stent, or Achilles tendons are the most commonly affected tendons. It occurs within weeks to months. More frequently on those who are older adults, those who are taking corticosteroids, fluoroquinolones, renal failure, or those who have previous tendon disorders. In these patients, one has to keep an eye and really assess the risk versus benefit of the treatment. So, bampydoic acid, plus azatomibe, or bampydoic alone, was approved in 2020 by the FDA as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous FH, or those with established ASCVD to lower LDL cholesterol. So, this slide really summarizes, generally speaking, if we have renal or hepatic impairment, generally this is not a concern not to use this medication. Again, if you have prior history of gout, as well as patients who may be at high risk of tendon rupture, it means that we need to monitor uric acid levels and make a judgment if this medication is okay for our patients. And then, of course, if a patient has really any joint pain, swelling, when they're using this medication, you stop it. As well as, if there is any pain that looks like tendon rupture, then be mindful of that. And again, this medication is not shown any, we do not have safety data in pregnant women or those who are breastfeeding. The last thing that we all need to remember, that these are all efficacy data. These are not effectiveness data. So, clear outcomes, which is the outcomes trial related to the use of this particular medication, is actually being performed in both primary and high risk, in high risk primary and secondary prevention patients. And interestingly, these patients have to have LDL cholesterol levels above 100, but these are really patients who are statin intolerant. So, we will really know the evidence in those patients, because right now, we don't have more of a class one kind of evidence in those patients. Mostly, it's observational data that we have. So, we'll all look forward to the results of this study, and hopefully, we will have a good follow-up of this, what Dr. Ballantyne was talking about. We're not gonna have a study that only has a two, three year worth of follow-up. Hopefully, this will have enough follow-up for us to really derive good conclusions from this. So, these are the take-home points. Studies show that bampidoic acid leads to 15 to 25% reduction in LDL cholesterol on background statins. Higher LDL cholesterol reduction in patients not on statin therapy. Combination of bampidoic acid and azetamide leads to about 35% LDL cholesterol reduction. The medication is not active in the muscle. Overall, it has good safety profile, with uric acid increase and small increase incidence of tendon rupture, and we are currently pending the CV outcome study for this particular medication. So, with that, thank you all for your attention. Thank you.

LDL cholesterol goals

bempidoic acid

non-statin therapy

musculoskeletal side effects

clinical trials