Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast Narrator - ? 00:11 is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk. Episode 119 I'm your co host, Dr. Kane, Dr. Khyati Patel 00:35 and I'm Dr. Patel, and the topic we are going to discuss is, what's the buzz about bempedoic acid for dyslipidemia, where we are going to discuss this new, latest and greatest treatment for dyslipidemia, and kind of dive into its pharmacology, its approved uses, and what the current clinical evidence as it stands. Dr. Sean Kane 00:57 And Dr. Patel, before we even started this episode, when you mentioned this particular drug, I had not heard of it at all, so I'm actually really excited to learn more about it. And given how common dyslipidemia is in terms of patients that are on statins and ezetimibe (Zetia) and things like that, I can potentially foresee this being a big drug that comes up a lot for anyone exposed to the healthcare environment in the future, given how common treating dyslipidemia is and how this is kind of a new feather in the cap of the treatment plan for these patients. Dr. Khyati Patel 01:28 And I agree with you, Dr. Kane, the buzz actually has been going on since 2019 and the FDA approved this agent in late February, early March of 2020 but you know, due to the current pandemic, the buzz was not really there, but it is, like you said, it's, it's one of the new kid on the block for the dyslipidemia treatment, and I think it's worth the attention for an episode. So let's get started with the patient case. That kind of puts the entire discussion in context. We have a Casey who's a 57 year old Caucasian female has a history of hypertension, dyslipidemia, even ASCVD had a coronary stent placed, has bilateral knee osteoarthritis and history of rotator cuff repair. About three months ago, she developed myopathy with her high‑intensity atorvastatin, 80 milligrams, so it had to be reduced to 20 milligram dose. That's the only medication she's on for her dyslipidemia management. And her most recent LDL was 105 as you know, with the history of coronary stent placement, the PCP prefers the LDL to be below 70, if possible. So the big question is, you know, what are the other options for her? Dr. Sean Kane 02:43 So, Dr. Patel, I think it's reasonable to very briefly, given that this could easily be a multi hour talk. Let's very briefly go through what are some of the typical dyslipidemia agents on the market, and what are their primary targets. Is it LDL or something different? Sure. Dr. Khyati Patel 02:58 I think that's a pretty fine background to cover. And so we, we all know statins are the go to therapy for the LDL reduction as well as the CVD risk reduction. We have Zetia with the similar outcomes as well. And then not, not the newest, but the newer treatment around the dyslipidemia arena are the PCSK9 inhibitors, which also help reduce LDL, are approved for ascvd risk reduction and also in those who have either heterozygous or homozygous familial hypercholesterolemia. Dr. Sean Kane 03:37 Then we also have things like bile acid resins that reduce LDL, but may or may not reduce cardiovascular risk. We have our fibrates, like fenofibric acid and gemfibrozil. We also have niacin. These are targeting high triglycerides, but again, controversial about cardiovascular benefit. Then we also have omega three fatty acids, these are indicated for hyper triglyceridemia, and with the Vascepa specifically, that particular formulation does demonstrate scvd risk reduction, whereas the other ones, the DHA EPA combo products, generally have not demonstrated that benefit. Dr. Khyati Patel 04:13 Yeah, and then these two probably not even worth mentioning, but there's a couple different products that were available, lomitapide and mipomersen for familial hypercholesterolemia. Most folks in the primary care may not have heard of it. Mipomersen is actually no longer available. It's been discontinued due to low sales in the US. It's still available in global markets. And then Lomitapide was one of those rare agents that was focusing on those who have familial type of hypercholesterolemia. Dr. Sean Kane 04:45 So Dr. Patel, going back to the drug they were talking about today, bempedoic acid, I think one of the first questions I had in my mind is, okay, so how does it work? And how is that different than, let's say, a statin? Dr. Khyati Patel 04:58 Yeah, and it's a great question, and I was. Really surprised when you know there was this buzz and kind of to learn what's the pharmacology behind it. And so we don't have to create a whole nother mechanism of action. You just have to look at the entire biosynthesis pathway for the lipids and look just a couple steps above where the statins work. That's exactly where the mempodoic acid is working. Essentially, it's an adenosine triphosphate citrate lies inhibitor, shortly called ACL inhibitor. ACL is basically an enzyme that converts citrate into a subsequent form that then, you know, goes to the HMG CoA, and then that's where your statins, the CO a reductase inhibitors, come in play, and then that, you know, further blocks the pathway for cholesterol synthesis. One thing to note, however, is that this agent is a pro drug, so it has to be converted to its active form in the liver by ACSVL1 enzyme. And for some reason, if you look at the manufacturer's website, they're really honing it on that this pro drug conversion is happening in the liver and not in the muscle tissues. Interesting. Dr. Sean Kane 06:18 So potentially down the road, I would assume that the marketing team may try to take advantage of that and say, because the drug is not activated in your muscles, potentially you don't see some of the myopathies and myalgias that you may see with statins. Dr. Khyati Patel 06:33 Yeah, and hold on to that thought, because there is like difference when we look at the safety profile when it comes to muscle related issues and compared to statins, but going back to this mechanism of action, so we all know that statins, the ultimate result is decreased LDL synthesis in the liver, and therefore you have this stimulation of more LDL C receptors on the periphery To absorb more LDL from the blood, and so the overall net result is decrease LDL levels in the blood. And this, this vampedoic acid, is doing essentially the same thing by working just a little bit upstream in the lipid biosynthesis pathway. Dr. Sean Kane 07:15 And Dr. Patel, as you mentioned, this was FDA approved in February of 2020, right before covid hit and it was approved as an add on to diet and then maximally tolerated statin, specifically for the indication of further lowering LDL levels in patients with heterozygous familial hypercholesterolemia, or in patients who have established ascvd, so people who have had heart attacks or strokes, or patients that have this genetic predisposition to very high LDL levels. Dr. Khyati Patel 07:45 And that's correct, this is really coming from, you know, all the different trials, and what kind of patient population was included, and they, you know, the outcomes that were actually assessed. So it's just that, yeah, by slapping the label of, you know, heterozygous, familiar hypercholesterolemia. It's opening up treatment options for people who actually have that condition as well. Dr. Sean Kane 08:07 Well, why don't we get into kind of the the nuts and bolts of how it got the FDA approval, what it looks like on the market, things like that. And of course, thinking of the PCs k9 inhibitors, my first question Dr. Patel is going to be, is this an oral product, or is it an injection product? Given that the PCs canines were injectables, Dr. Khyati Patel 08:25 that's correct. And this is where probably a slight advantage of bempedoic acid comes in in play. There's a couple of different formulations available, and both of these are oral tablet formulations. So a brand name of Nexletol is your plain bempedoic acid, only one tablet, one formulation, 180 milligram strength available. There is another combo product available with the azidime or zedia. So bempedoic acid plus azidime, and the brand name is next Lisa, again, with each having just one strength available in the market. You get it by bempedoic acid 180 milligrams plus ezetimibe 10 milligram tablet. That's also a simple ones daily tablet product. Dr. Sean Kane 09:11 And just like many new products that are on the market in terms of hepatic and renal adjustments, there's no adjustment for mild to moderate hepatic impairment, and they didn't really study it, and those with severe cirrhosis or hepatic impairment. And then for renal there is no adjustment for mild to moderate disease. It's under studied in those with Crete and clearances less than 30, and basically not studied in those receiving dialysis. So again, this is very typical of a very new drug on the market that we don't have some of these special patient populations that may have kinetic differences that may confer some dose adjustment. We just don't have that data yet correct. Dr. Khyati Patel 09:47 And you know, one of the pertinent kinetics we covered was that it was a pro drug, and it's converted to an active drug in the liver. Another kinetic that's more important is to look at the metabolism so it. Got it doesn't have CYP metabolism, so we're not looking at any CYP interactions, but it does get metabolized into an inactive glucuronide form, or conjugate by the glucuronide conjugation process. And so this glucuronide conjugate is actually the inactive component, but the parent drug, as well as the active metabolite, they named it, ESP something, those two are the one that render benefit. Dr. Sean Kane 10:30 So Dr. Patel, of course, the main thing we're going to be interested in is, one, does it reduce LDL? Two, does it reduce LDL when you have a statin on board already? And three, the big question is, does it reduce cardiovascular risk? So what can you tell us about the data that we have so far, given that it's a fairly new drug on the market? Dr. Khyati Patel 10:49 Yeah, so you know, in 2019 when the bus started, was really, you know, preliminary, promising data for plenty of phase two studies. But if you look at phase three data, that's where you know what FDA is looking for in order to approve a drug, the clear group trials is what they looked at and clear that acronym stood for cholesterol lowering via bempedoic acid and ACL inhibiting regimen. So they had a slew of clear trials like tranquility and serenity that looked at just LDL lowering. So essentially, the trials were designed for 52 week and most of them were looking at 12 week reduction in the LDL compared to placebo. In these patients, they were on maximally tolerated statin. And what do we know about statin intolerance, or what does it mean to be on maximally tolerated statins. It could be mild intensity statin. It could be no statin at all, because, you know, that's their tolerance, that they cannot tolerate any statin. So the range of the statin background therapy was different. We're going to talk about that in a pooled analysis in just a little bit. But looking at week 12, when compared to the placebo, we saw anywhere between 21 to 28% reduction when patients were on the bempedoic acid therapy. Dr. Sean Kane 12:15 And was that when they also received zedia on top of it, or was it without or how did they what was the background therapy on those patients? Dr. Khyati Patel 12:22 Yeah, some, some patients in the tranquility trial had was, was like the add on to the Zetia and the Serenity trial, you know, there was add on to other statin therapies and, kind of like variety of non statin therapies as well. So it's kind of hard to pinpoint exact percentage patients who were on on ezetimibe, but you could say that some patients were definitely receiving that treatment. Dr. Sean Kane 12:47 So Dr. Patel, that was in a patient population who had higher LDLs, above 100 that were receiving basically Max therapy, not PCSK9 Max therapy, but Max therapy with statins and plus or minus ezetimibe. And then we looked at their LDL reduction. What other trial data do we have specifically, maybe in patients that are at a higher risk for cardiovascular disease down the road? Dr. Khyati Patel 13:12 Right? So then came couple different trials, clear wisdom and clear harmony that involved patients with established ASCVD or history of heterozygous, familial hypercholesterolemia, or both, who had, you know, elevated LDL levels. Again, these patients were were to be on maximally tolerated statin. And then again, study design was very similar, looking at them at 52 weeks, but then the first evaluation of LDL reduction occurred at the 12 weeks, and so what they found, again, is anywhere between 15 to 18% reduction in the LDL level from baseline when compared to placebo. And these results were statistically significant, Dr. Sean Kane 13:59 so again, fairly similar LDL reduction to what we saw with our previous studies. And Correct. Dr. Khyati Patel 14:05 That's absolutely correct. And if you're wondering, you know these patients had a CVD. Were they on statin or not? Yeah, they were. 94% of the patients in the wisdom trial had ASCVD. 53% of these patients were on high intensity statin. 31% of these patients were on moderate intensity statin in the harmony trial, you know, in addition to maximally tolerated statin therapy, they were allowed to be on other nonstatin lipid‑lowering agents such as ezetimibe and fibrates. However, these percentages weren't very high. You were looking at 8% of patients on, you know, ezetimibe, and 4% of patients on a fibrate therapy. Dr. Sean Kane 14:44 So, Dr. Patel, you know, in thinking about the mechanism where we basically have a drug that's just working a little bit upstream of the same pathway that statins work, I think it would be reasonable to have assumed, prior to having this data, that perhaps there is an interactive effect, meaning, if. You're on a statin, maybe the bempedoic acid doesn't work as well. Or if you're not on a statin, it works better. It sounds like even if you're on a statin, you get an additive effect. It's not like the statin effect neutralizes out the effect of our bempedoic acid, or vice versa, even though they're on the same pathway. Then yeah, Dr. Khyati Patel 15:16 you actually bring up a really good point. My initial thought when I reviewed the mechanism of action and how it works on the same pathway was exactly the same. Does it render any additional benefit to the statin, you know, and and currently, the data we have is only to talk about that surrogate marker. Does it lower LDL or not, as we will discuss that, you know, the cvot outcomes, the cardiovascular outcome trial is still pending. It's still recruiting patient, and so we don't have that cardiovascular morbidity and mortality data out yet. But if you just look at plain old LDL reduction, yes, it's surprised to see that it has, you know, somewhere around 2018, to 20% additional LDL reduction we are getting in addition to, like, maximally tolerated statin. And of Dr. Sean Kane 16:05 course, in my head, I'm thinking, okay, so what if we just doubled our statin dose or something to that effect? And the reason that that won't work is that at some point you're going to start having some of the adverse effects of the statin worsen, right? So this is a way to get additional blockade of this similar pathway of cholesterol synthesis without potentially having more of the side effects of just increasing the statin dose, then Dr. Khyati Patel 16:31 that's correct. And if you look at the baseline population in the studies, as well as look at what the FDA has approved it for, FDA has approved it for those who cannot be on max tolerated, you know, maximum dose of the statins, maybe they're on just little dose of the statins. And and somebody who needs additional LDL reduction, right? And so somebody who tolerates the statins, okay, their LDL is controlled, just okay. There is, to me, there is no reason for us to go out and change them to bempedoic acid or add additional bempedoic acid on top of it. So really, the angle they're taking it is those who cannot tolerate statin and still need additional LDL reduction. And so it would be a miss if we did not talk about clinical outcome of a trial that looked at a combination therapy for Zetia and the bempedoic acid, knowing that there is a formulation the Nexlizet out. This was a trial, again, phase three trial, looking at that one's daily regimen of combo medication, 180 milligram of bempedoic acid, 10 milligram of Zetia. And when they looked at the outcomes, they kind of divided into four different groups. This combo group looking at bempedoic acid alone, looking at Zetia alone, and then looking at placebo. And what does placebo really mean? It really means that patients might have been on that background Max tolerated statin therapy, and what they found at 12 weeks that the combination therapy lowered LDL levels by up to 38% Dr. Sean Kane 18:02 and this would be consistent with what you might expect to see versus placebo. When you have ezetimibe, which roughly gives you between a 15 to 20% reduction, and then bempedoic acid, which, again, we said, is roughly about another 20% reduction. So combined, you're getting this additive effect, which I think is something that you might expect to see, and it's nice to see that that actually was born out in the trial. Dr. Khyati Patel 18:23 Yeah, absolutely. And again, you know, they're both working. And, you know, the target, but two different mechanism of action produces larger results, and that that does exactly what this trial proved. So kind of, Dr. Sean Kane 18:34 you know, 30,000 foot view. Dr. Patel, what is the general LDL reduction that we're going to see? And then did these trials look at any other biomarkers that we know are associated with cardiovascular disease, like CRP, or any of our other lipid numbers? Dr. Khyati Patel 18:50 So none of these larger trials looked at individual biomarkers. But then there was this pooled analysis, and for those listeners who are interested in reviewing that, we have a citation in the reference section, the biomarkers were that were looked at, in addition to LDLs, we're looking at total cholesterol, the non HDL, the Apple B and the high sensitivity C reactive proteins, all of these biomarkers actually showed significant reduction, you know, like, I think p value was less than point 001, on pretty much All of these, which are surprising. But then you as a clinician, you think and wonder is like, really, does that translate into the meatier outcomes, such as, you know, reduction in morbidity and mortality? And we just don't know that yet, perhaps the outcomes trial is going to produce that. That's going to be completed in 2022 Dr. Sean Kane 19:40 so really, at a minimum, it's nice to see that these biomarkers had favorable trends, but we would like to see those clinical outcomes. Dr. Khyati Patel 19:47 Then what this additional pooled analysis of the four trials showed is everybody's interested in okay, if the statin intensity. Made any difference or not right? So they kind of pull the statin intensity into two different categories, the moderate to high versus no to low. As expected, for those who are on no to low intensity statins, there was a higher LDL reduction at week 12, about 24% but if you even your patients were on moderate to high intensity statin, they still got away with at least additional 17 some percent decrease in their LDL from baseline. Dr. Sean Kane 20:28 So basically, Dr. Patel, you know, if you're already on a very high intensity, high dose statin, you're going to get a couple percentage point less reduction in LDL reduction compared to if you were on a low or no statin. But really, we're still looking at roughly a 20% reduction on average for most patients. Unknown Speaker 20:44 Then, right? Oh, that's absolutely right, right. Dr. Sean Kane 20:47 So one additional question that comes to my mind is glycemic control and diabetes. You know, in the past five to 10 years, it's kind of become a hotter topic with statins, in terms of statins potentially worsening glycemic control or causing patients to have a new diagnosis of diabetes. Have we seen a signal like that with bempedoic acid? Dr. Khyati Patel 21:09 Yeah, and that's where I think these pooled analysis, you know, whether this was the deed of the manufacturer themselves, that came in handy. None of these trials looked at glycemic control as their even primary or secondary markers. But they had a pooled analysis of four trials that looked at about 3600 patients, particularly for 12‑week A1c and blood glucose control, and they found that bempedoic acid did not cause new onset diabetes or worsen the blood glucose control in those who already had diabetes. And so this differentiates bempedoic acid in itself, from statin. What we need to worry here is that this was a 12 week analysis. Things could be a little different when we're looking at it a little longer term. And so hopefully the longer term CVOT trials have looking at the AUC and blood glucose levels as one of their biomarkers or one of their outcomes, and so we would be able to see if there is a longer term effect on the glycemic control. Dr. Sean Kane 22:14 So Dr. Patel, I bet you $1 the drug company is already running that big, large cardiovascular outcomes trial as we speak, right? Dr. Khyati Patel 22:23 You know it? Yes, it's like one of those, you know? Yes, it was good enough to have a phase three trial, just with LDL reduction for just getting your foot in the door, you know, with the FDA approval. But you know, every clinician is going to look at the bigger outcome, the meatier outcome, and that's their morbidity and mortality data. So you're right. There is a recruitment for a phase three trial named CLEAR Outcomes. One of those CLEAR group trials started in 2016; it's anticipated to complete recruitment by 2022. They're kind of hoping to get around n of about 10,000 patients and hoping to look at that primary composite outcome of, you know, your standard major outcomes, such as, you know, composite of CV death, nonfatal MI, stroke, any coronary revascularization, and such as that. So a few more years to wait until we know for sure if this drug is doing anything in terms of the M and M outcomes. Dr. Sean Kane 23:27 I think it's worth mentioning as well that in the package insert appropriately so the FDA does have a statement under the indication section that says limitations of use the effects of this drug on cardiovascular morbidity and mortality has not been determined. And Dr. Patel, prior to recording you had mentioned that this is also the same comment that the PCSK9 inhibitors had until they actually demonstrated cardiovascular benefit. So especially given the issues historically that we've had with surrogate endpoints, especially in the diabetes world, it is really nice to see that there is at least a comment on the package insert saying it was approved mostly for a biomarker, but we would love to see some cardiovascular outcomes data to come out in the future, and it's not yet indicated for that particular indication. Dr. Khyati Patel 24:12 Yeah, and I think it's an it's a neat move. Another reason I think that FDA might have done it is because in in the actual use approved label. It says, you know, and those who have established ascvd, and so maybe they want to make it sure that the readers don't look at it, because it's approved for those who have established ascvd, that it doesn't necessarily render the benefit. We just haven't seen that yet. And so I think they're just trying to make sure that they differentiate the two. Dr. Sean Kane 24:41 That's a great point. So that's the efficacy side. So we've kind of established LDL reduction here. Of course, the next thing we talk about as pharmacists is a safety profile. So what kind of side effect profile are we observing with bempedoic acid? Yeah. Dr. Khyati Patel 24:56 And so, you know, most of these trials were 52 week trials, and. That's where the side effect profile is coming from. So not not a very short term period, but not a very long run trials, either. And so most common side effects were upper respiratory tract infection, muscle spasms. This is not muscle like myalgia muscle spasms. It's a little bit different than statins. Pain was commonly reported specifically back pain, abdominal pain and discomfort, and then pain in the extremity as well. Other reported side effects were anemia and then elevated LFTs, which is kind of like your statin therapies too, right? And so baseline monitoring as well as periodic monitoring in those patients may be important. Dr. Sean Kane 25:43 You know, Dr. Patel, one of the challenges with a brand new drug is really fully appreciating the side effect profile. And we, you know, we've covered this many times on this podcast before that, from the FDA point of view, they have to mention any side effect in the packaging that meets certain criteria, so numerically more common, or more than 1% more common with the drug versus the comparator above a certain incidence rate, things like that. So we actually don't for sure know whether bempedoic acid, for example, truly does cause upper respiratory tract infections, but numerically, we did see an effect. So causation versus kind of a type one error is hard to determine at this point, and as we get more and more data, we'll be able to really fully appreciate whether this is background noise or truly a side effect profile of the drug. Dr. Khyati Patel 26:27 You're absolutely right. Dr. Kane, you know, it takes years of clinical experience, aka phase four trial, to put any clinical context to some of these laundry list of ADRs that you know have to be on the FDA label because these were observed side effects in the clinical trials. So you're absolutely right. One exception to what you just said is elevation in the uric acid, so hyperuricemia, that was one of the commonly reported in 3.5% of the patients who were in the bempedoic acid therapy group, versus 1.1% in the placebo. We're going to talk a little bit more about gout and the elevation of uric acid in just a little bit. But yeah, that was kind of like the exceptions we needed to point out. Dr. Sean Kane 27:12 And we should also mention, you know, one other way that you can also look at a side effect profile is, what percent of the time did someone stop the drug discontinue it during the study period because of a particular side effect, which is basically a surrogate for a particular side effect that the patient or the provider feels is associated with the drug that was so bad that they wanted to stop enrollment in the trial. So this did occur a little bit more commonly with bempedoic acid versus the comparator placebo. It was 10.9% versus 7.1% that patients decided to stop therapy because of a side effect, and some of the more common reasons was muscle spasm, diarrhea and pain in the extremities, although, again, the actual rate of these things happening was basically less than 1% so there isn't a particular smoking gun, if you will, in terms of one side effects, with the exception of uric acid, that we'll talk about in a second, that is very clearly associated with this drug, right? Dr. Khyati Patel 28:12 And then some of the side effects that occurred worth, again, kind of worth mentioning in the FDA approved label, but happened with very less frequency where atrial fibrillation and benign prostatic hyperplasia, again, the clinical relevance of these two is still not established. We might see more data come out from one of those longer CVOT trials. Dr. Sean Kane 28:35 And if we look at the combination product of bempedoic acid plus ezetimibe, we see kind of a similar story. So kind of this background noise, potentially of UTIs, nasopharyngitis and constipation and again, more data is going to be helpful to really decide if this is true or something that's just more background noise. Yeah. Dr. Khyati Patel 28:53 And some of some of these three are actually established side effects with, you know, Zetia, we know as ezetimibe we have years of experience with that now. So kind of sort of say, like not surprised that it's coming in the combination product, but it's there, and it's mentioned in the Nexlizet PI as well. Dr. Sean Kane 29:12 Well, Dr. Patel, let's get back into that hyperuricemia, because this is one of those very interesting side effects that potentially I would not have expected or anticipated to see. And I would say that the data definitely does support this for sure as a potential adverse reaction to bempedoic acid. Yeah. Dr. Khyati Patel 29:29 And again, the cause is kind of unknown. They're kind of blaming it on some of the drug interaction that bempedoic acid has in terms of one of those transport proteins like the oats and maybe that explains some of the elevation in uric acid. But yeah, the numbers are definitely emerging to be different. The Gout precipitation. We're not just talking about uric acid elevation, The Gout precipitation can occur early. In the treatment, and it could persist as the treatment goes. And if you look at the instances of got reported collectively in all the trials they have so far, it was 1.5% in bempedoic acid group versus point 4% in the placebo group. And obviously the risk of these events and the attacks were higher if somebody had a previous, you know, past medical history of gout, so like 11.2% of the patient versus 1.7% in the placebo group. Dr. Sean Kane 30:30 And Dr. Patel, for me, that number really stood out, and that if you already have gout, and you take the strike, you're way more likely to have a gout attack during that 52 week period, versus someone who does not take bempedoic acid. So clearly, you know, patients should be aware of this if they already have gout, and I would see this as a great opportunity for shared decision making in terms of the risk of gout attacks and how painful those are, and a patient's individual risk versus the potential benefits at this point of LDL lowering, and potentially in the future, if the drug demonstrates cardiovascular disease reduction risk, then potentially that would be a great opportunity to chat with a patient about risks and benefits of starting the drug therapy or not. Dr. Khyati Patel 31:12 Yeah, and then perhaps the evidence is just not enough for them to include gout as one of the contraindication to the therapy, because I even read that, you know, if epitomic acid is appropriate therapy, then you know, when the patient has elevation of uric acid or got precipitation, consider your lowering therapy. But to me, it's like you're trying to kill side effect of a drug with another drug, and it just doesn't well. But they may have said that right now, just because, you know, we have much little data, but in the longer trials, if this becomes more prominent, they may move gout as one of the contraindication or do not use If so and so list and Dr. Sean Kane 31:53 Dr. Patel, if you really want to jump down the rabbit hole, you lauric fabuxistat has an issue with cardiovascular disease risk right now. So there's a whole nother aspect of this, which is, if you have poorly controlled gout with this drug, does that potentially change the benefit that you'd see from bempedoic acid because you're having gout that is less controlled or not? We don't know the answer to that, and that's a whole nother issue that I think would really need to be investigated to see whether this exacerbation of gout confers some increased risk of cardiovascular disease versus not, right? Dr. Khyati Patel 32:29 And I think that's, that's absolutely right. Great point to mention. And I'm going to go back and stress the importance of the shared decision making, you know, and regardless of that in any patient, they're saying, go ahead and monitor the uric acid levels at baseline, and then even consider, you know, ongoing uric acid level monitoring, again, quote, unquote, periodically, is what they're saying. We don't have any sort of guidelines saying how frequently that needs to occur. Dr. Sean Kane 32:56 So then the other warning that comes in the package insert deals with tendon rupture, and what they found was a 0.5% risk with bempedoic acid versus zero with placebo, they saw Achilles tendon rotator cuff and biceps tendons, and this could occur weeks to months into treatment, a couple of risk factors that are pretty consistent, risk factors with other drugs that have this similar warning would be older age, above 60, history of tendon disorders, renal impairment and concurrent use of corticosteroids or fluoroquinolones. And basically the recommendation is that you shouldn't use bempedoic acid and those with a history of tendon disorders, including tendon rupture, and you should stop the drug as soon as any tendon issue is suspected for a patient. Dr. Khyati Patel 33:39 Yeah, and that's that's a very interesting warning to pay attention to. You know when, when these kind of started to come about in patients who are taking fluoroquinolones? Were like, Oh, this is happening once in a while. And then it blew out of the proportion, and it was blaring corn everywhere. Like, do not use and those who have you know tendon issues, you see first sign of tendonitis, go ahead and stop the fluoroquinolones do not, you know, re expose them. And I think bempedoic acid is kind of right there where, you know, we just don't want to take any risk in these patients. Dr. Sean Kane 34:10 So switching gears a little bit. Dr. Patel, earlier, you said that we don't have to worry about SIP interactions, but it does sound like there are some interactions that we do need to be aware of. And I actually had to go back all the way to pharmacy school to really reevaluate some of these unique non SIP interactions that I either forgot about or never learned about. So I'd love to hear more about this. Dr. Khyati Patel 34:29 Yeah, absolutely. And I think what you're referring to Dr. Kane is the transporter mediator drug interaction like the oats and so lepidoic acid has been known to be a weak inhibitor of the oat three and oat two and some other subset of oat enzymes, as we mentioned. This probably explains some elevation in the in the uric acid, but basically, these are transported proteins that are expressed on the hepatocyte that uptake the drug molecules for metabolism. And the idea is that, you know, there is this, this inhibition then means that the drug is not going to be uptaken for metabolism, and more drug is going to be, you know, available in the blood, leading to more side effects and, you know, interactions and things like that. So what, what the package insert is saying is that even with this weak interaction. We don't really know the clinical significance of actual drug drug interaction, but they're saying that probably that's where the underlying mechanism of uric acid elevation comes in play. Dr. Sean Kane 35:34 On top of that, we do know that there are some statin based interactions, specifically with sevastatin and pravastatin. The package insert said that roughly this can double the same concentrations of your simvastatin or Prava statin. So they actually recommend that you don't exceed some 20 milligrams or 40 milligrams of pravastatin, obviously, because of the risk of myopathy. So if you suddenly double your statin dose in your blood, you're going to be at a higher risk for dose dependent side effects like myalgias, myopathies, things like that. Yeah. Dr. Khyati Patel 36:03 And then particularly, they looked at the area under the curve, and there were like, two fold increases for both of these statins. And it's actually surprising to see that that's the case for Prava statin, because we consider Prava as like, the mellowest of all the statins when it comes to drug interaction. So poor Prava statin is in this category now. But the good news is that our high intensity statin, which is what most of our patients would need, like atorvastatin or rosuvastatin, do not have such high increase in AUC, and therefore we don't have to do dose adjustment when we are using it with bempedoic acid. Dr. Sean Kane 36:40 And if you're like me, where sometimes I have a tin foil hat and I'm thinking about like, conspiracy theories and things like that, the next thing that came to my mind Dr. Patel was well, for giving a drug that doubles statin concentrations, is that explaining some of the LDL reduction that we're seeing in these clinical trials? And the answer is probably no. And the reason for that is that a general rule of thumb for doubling statin doses is that when you double a statin dose, that your LDL reduction goes down by about 6% so even with a doubling, we would expect to only see a 6% reduction in LDL, not roughly a 20% reduction. So the bempedoic acid is still doing stuff, aside from just increasing statin exposure for the patient. Dr. Khyati Patel 37:27 And I love that tenfold hat input. Dr. Kane, it's absolutely worth thinking. As a pharmacist, you know, we think about this pharmacologic impact and stuff, and so it's worth, worth the discussion. Thank you. Dr. Sean Kane 37:40 What about drug interactions with the combination product? Dr. Patel, yeah. Dr. Khyati Patel 37:45 So with Nexlizet, which is that combination with ezetimibe, they're looking at mainly three additional drugs that we need to be careful with cyclosporine, which we know cyclosporine has drug interaction with pretty much all the drugs out there where there is an increased risk of exposure to both the Nexlizet and cyclosporine itself. With fenofibric acid, there was an increased risk of cholelithiasis, but because of the increased secretion of cholesterol in the bile. So I know formation of the bile, bile stones, in Dr. Sean Kane 38:19 terms of special populations probably shouldn't use this in pregnancy, right? Given that we know that statins are inappropriate for pregnancy, we're working in the same pathway. So this is really a no go for patients who want to be pregnant or who are pregnant, correct? Dr. Khyati Patel 38:35 Absolutely right. We don't have evidence, obviously, because these patients were not included in clinical trials, but they're willing to bet their money that just because it works right upstream of that statin pathway, lipid synthesis pathway, and that that's this is going to be the same effect as the statins. And those who are pregnant and so do not recommend the use, and again, they're not recommending the use and lactating mothers either, just like the statin therapy. Dr. Sean Kane 39:02 So of course, with every new drug that we ever talk about on helix Dr. Patel, it almost always comes down to cost, in terms of probably the biggest rate limiting factor for a patient to be able to be eligible for a drug. What kind of cost are we looking at for bempedoic acid, Dr. Khyati Patel 39:18 so for bempedoic acid, it's oral, so it's not as crazy as our injectable counterparts in the pcsk Nine inhibitor therapy, thank God. But the the average wholesale applies is coming out to be about $13 per day, which is like $13 per pop. It's about $400 per month. Dr. Kane, I believe you quickly looked into good RX, and you found that average cost was about $330 per 30 day therapy. If we compare that to some of our other options for LDL reduction and also CVD risk reduction, like the atorvastatin or the you know, the ezetimibe, obviously generics. We're looking at a. Nine bucks for 30 day therapy for atorvastatin, perhaps 10 bucks for 30 day therapy for our, you know, generic ezetimibe. So definitely these are bempedoic acid is expensive than our statins and ezetimibe. But if you flip the slate a little bit and look at our PCSK9 inhibitors, definitely cheaper than those. The PCSK9 agents are running about $450 per month worth of therapy. Dr. Sean Kane 40:29 Interesting, so it seems like they're just a little bit lower price than those PCs k9 inhibitors. And of course, from a patient perspective, to take one tablet a day is probably going to be favorable to inject in yourself, no matter how often you have to inject. So I for sure can see a place in therapy, and it seems like they've probably priced it as smartly as they could to still make a profit on the drug as well. Dr. Khyati Patel 40:51 I think so too. I think that was a smart move. You know, putting putting all those like efficacy, safety input, and then looking at the cost too. You know, we are always inclined to look at our guideline makers and see, like, okay, what are these experts have to say? You know, have there been any incorporation in the guidelines? Honestly, there is nothing in the guidelines yet. As we know this, epidemia guidelines tend to be slow to update. Anyways. So I'm hoping, though, however, with the next update, that they will mention bempedoic acid, and perhaps after the outcomes results from the morbidity and mortality data, that there might be some substantial changes in the guidelines. Dr. Sean Kane 41:32 Well, Dr. Patel, clearly, the guidelines are not out, but I think you and I, based on the data that we've looked at and kind of what we've covered today, we can probably look into our crystal ball and think about what might come out of the 2021, guidelines, or whatever year they end up coming out. What are some comments that are likely to be in those guidelines when they do come out? Dr. Khyati Patel 41:54 Yeah, and so I was thinking like, you know, where do I see this drug in the plates of therapy? And so few things to kind of keep in mind that, hey, it's mechanism action is pretty similar to statin, just kind of works above the pathway where statins are working. They're giving additional LDL reduction when added to maximally tolerated statin, as we have discussed, kind of differentiates itself from statins and couple of the ADR categories, you know, doesn't have that stand induced myalgia. There is muscle spasms, but it's not similar to the statin myalgia. So those who have intolerance to statins because of myopathies and myalgia, they could be on bempedoic acid in the short term data, looking at the ANC and blood glucose elevation, you know, they found that bempedoic acid did not cause that. Again, this was pooled analysis and not looking at a study outcome, which we know is a known risk with the statin, especially high intensity statin therapy. So it kind of differentiates itself from statin in a couple different areas like this. Dr. Sean Kane 42:59 And of course, on the downside, you know, statins had no issues with patients who had gout or tendon rupture, and that potentially, is something that we need to be aware of. For sure, is something that we need to be aware of with tendon rupture and then gout, probably not a great idea in most patients with gout, but I think we probably need a little bit more data with Dr. Khyati Patel 43:17 that correct. And we kind of just talked about the cost, and so it's going to be somewhere right in the middle, not not as cheap as statins or ezetimibe but not as expensive as the PCS canine inhibitors, either. But right now, as we're speaking with the, you know, CVOT trial still ongoing, it's important to add that, you know, this is just approved for the LDL reduction. We don't have any data on the morbidity and mortality evidence yet to speak about which can change in future. Well, why Dr. Sean Kane 43:47 don't we go back to miss Casey, our patient who we were kind of evaluating what our treatment options were for that patient. And you know, just as a reminder, she was 57 years old, had a history of ascvd. She couldn't handle torver statin 80, so now she's on 20. Her LDL was 105, and we would like it to be lower. So Dr. Patel, what are your thoughts for that particular patient? Dr. Khyati Patel 44:10 Yeah, and so, you know, talking about bempedoic acid, we want to put our hats on and think whether that would be beneficial, you know, if we add it to the 20 milligrams. So we do know that based on the discussion we've had, there is evidence for concomitant use with further LDL reduction. You know, there is no drug interaction to be seen with atorvastatin. We don't have to worry about dose adjustment, and it's a simpler ones daily regimen for both agents. So we're not talking about, you know, a lot more added pill burden on top of it, the concern, however, and the biggest one for me with bempedoic acid it would be her history of having a previous rotator cuff repair, as we covered it basically says, you know, if you have history of tendon ruptures, or any signs of tendon ruptures, you know, we should not be using this drug. We should just. Continue it. So perhaps for her, I wouldn't really go with bempedoic acid, just based on that history. Dr. Sean Kane 45:06 So then, if you're not going to go with bempedoic acid, you know, can we offer her anything else that would give us some of the cardiovascular benefit the LDL reduction that we're trying to look for, given that she does have risk factors and her LDL is not where we want it to Dr. Khyati Patel 45:20 be, right? And so a couple of different agents that are available in our pocket are, you know, ezetimibe or the PCSK‑9 inhibitors. Now, PCSK9 inhibitors are, like we discussed, expensive. They're injectable therapy versus ezetimibe is one's daily PO therapy. It's cheaper. It has evidence for, you know, decreased cardiovascular morbidity and and they improve it trial. And so why not add ezetimibe And hey, to kind of add to it, there is a combination of atorvastatin and ezetimibe available. So we can just combine her pill into one, and she can just simply take that once a day. Dr. Sean Kane 45:56 I think that that sounds really good. And Dr. Patel, I wanted to thank you for bringing this new drug. To my attention, as a inpatient critical care pharmacist, I've actually prior to today, never even heard about the drug, so I hope other listeners also benefited from a drug that is likely going to be a very big deal in the near future, especially if any of that cardiovascular outcomes data does come about. You're absolutely right. So with that said, if any of the listeners want to know more about the drug, we do have links on our website, HelixTalk.com click on episode 119 and you'll be able to see links to some of the clear trials and get more information about the drug. We're also on Twitter at HelixTalk, and you can follow us there for clinical pearls of many of our past episodes. And we love the five star reviews in iTunes. So keep those coming. You can always contact us through the website if you have any episode requests or anything that you want to chat about. So with that, I'm Dr. Kane and I'm Dr. Khyati Patel 46:49 Dr. Patel, and as always, study hard. Narrator - Dr. Abel 46:52 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 47:04 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.