Speaker 1 00:00 Alex, welcome to HelixTalk, a podcast presented by the Rosalind Franklin University, College of Pharmacy. We're hoping that our real life clinical pearls and discussions will help you stay up to date and improve your pharmacy knowledge. 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. And now Narrator - Dr. Abel 00:29 on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk. Episode 33 I'm your co host, Dr. Kane. I'm Dr. Schuman, and I'm Dr. Patel, and this week we're talking about a newly approved drug class called the PCSK9 inhibitors, with a particular focus on the one that was first approved by the FDA recently. Speaker 2 00:49 So that agent is marketed as brand name of Praluent, alirocumab, and this was approved by FDA in July 2015, another agent of the similar category is evolocumab, or Repatha, and that one is approved in August 2015 Dr. Sean Kane 01:08 So normally, when I think about newly approved drug therapy, generally speaking, some of the new drugs that make it to the market aren't really game changers, if you will. So if you go back a couple episodes we talked about, kind of some of the drugs and drug classes over the past 20 years that we really felt like we're game changers, and I could view this as a potential game changer, this new drug class that we're talking about today. Speaker 2 01:28 Yeah, let's see. Let's look into more of the clinical trials, the evidence behind them, and see if you can really call it a game changer. Speaker 3 01:36 And it certainly, I believe, has some of the way it's come about. It fits into some of that game changer kind of criteria. So it's a medication that in 2003 just to go back a little bit, there was they were studying these mutations they found in individuals with cholesterol dysfunction. They found this gain of function mutation in the gene encoding what's called PCSK9, and that stands for proprotein convertase subtilisin kexin type 9. So we'll just call it PCSK9. Probably a good idea. Yes, yes. So we'll just from here on out. We'll shorten it. But what they found is that resulted in this familial hypercholesterolemia. So when there's a gain of function mutation, sometimes they're also loss of function. And these loss of function mutations were discovered later, and it led to one case of adult they found with an LDL of 14. And then population studies showed that about 2.6% of African Americans, 3.2% of Caucasians had one of these loss of function mutations, and then reductions in both LDL, and interestingly, in incidents of CHD as well. And so what they decided to do is make an isolated human monoclonal antibody to lower the LDL by targeting that enzyme and to load the LDL in adjunct to diet and also in presence of a maximally tolerated statin dose, Speaker 2 02:55 so in terms of the receptor activity and mechanism of action. Yes, this could be a game changer. But like you just mentioned, Dr. Schuman, the current approval is with diet, obviously, with any kind of dyslipidemia, but also in conjunction with maximally tolerable statin dose. So we're not talking about this medication being used by themselves. They've studied them with statins. Dr. Sean Kane 03:18 So right now, Praluent, or alirocumab is really only FDA approved in addition to a statin therapy, but certainly down the road, one of the areas that we're going to be more interested in is not only in addition to a statin, but in the patients that don't tolerate a statin for whatever reason, usually due to myopathies. This could be kind of one of those agents that a patient can get big LDL reductions, and hopefully big reductions in cardiovascular endpoints if they can't tolerate a statin. Speaker 2 03:44 So when we look over the efficacy and safety evaluating some of the trials, you'll know currently there is no cardiovascular morbidity or mortality benefit, but like you said, Dr. Kane, there could be future possibility. There are some ongoing trials that are long term enough to establish these outcomes, Dr. Sean Kane 03:59 Just to kind of unpack the mechanism again a little bit further. So this PCSK9 protein is kind of the bad guy. We want to get rid of it. So normally, LDL binds to an LDL receptor on your liver, and that LDL receptor pulls in that LDL and brings it out of your blood. PCSK9 is a protein that goes after that LDL receptor and basically removes it from being able to pull LDL out of your blood. So that means that if you get rid of or inhibit PCSK9 these LDL receptors will stay on the liver and be able to pull in LDL from the blood into the hepatocyte. Right? Speaker 3 04:33 They have this kind of, just like a lot of systems in the body, they have these checks and balances in place. So there have been some studies they found that showed that statin use can actually up regulate some of those LDL receptors and also increase expression of PCSK9, again, part of this negative feedback loop. So then the theory is that by inhibiting PCSK9, alirocumab could prevent the LDL receptor degradation, and thus the LDL receptors continue to do their job to capture that floating LDL and get rid Dr. Sean Kane 05:02 of it. So when we talk about a monoclonal antibody, which is specifically structurally designed to go after this PCSK9 bad guy, if you will, I'm guessing it's not an oral formulation. Then if it is coming as a monoclonal antibody, Speaker 2 05:15 and that's absolutely correct, it's given as a subcutaneous injection every two weeks, so most patients will be started on a 75 milligram dose every two weeks, and then, depending on the LDL response that's checked about four to eight weeks, they can increase the dose to 150 milligrams every two weeks. And two different formulations are available. There is auto injector or a pen injector, and then there is a pre filled syringe as well. Dr. Sean Kane 05:43 So Dr. Patel, will patients be doing this in the comfort of their own home, or do they need to go into a doctor's office every two weeks? Speaker 2 05:48 Currently, because it's a subcutaneous injection technique, if your patients are never used to taking subcutaneous injection, it will be advisable to maybe have their first dose be at the clinic. But as far as the safety perspective, there is no current recommendation that this first dose should be given in a doctor's office or at a medical facility. Dr. Sean Kane 06:07 So hopefully, once a patient becomes more accustomed to the drug, then they'd be able to do it in their own home. It's not like some of the other agents where anaphylaxis is a big concern, that they need to be observed after receiving a Speaker 2 06:17 dose or something like that. Absolutely. And we'll look at the safety issues with this too. It is a monoclonal antibody which can mount some of the allergic response. However, currently there is no provision for that intense monitoring with the first dose. So if Dr. Sean Kane 06:33 we go back to our discussion a long time ago, when we talked about the new lipid guidelines, we talked a lot about the difference between improving your numbers as a surrogate endpoint, and then improving your cardiovascular risk, which is a clinical endpoint. So can you, Dr. Patel, talk more about kind of the difference in what we're seeing now and what we'd like to see in the future with these PCSK9 inhibitors? Speaker 2 06:54 So currently, like we mentioned, there is no cardiovascular morbidity or mortality benefit. All they have looked at in the current trials, is looking at how much LDL reduction we're getting. We know the evidence show that if we go after LDL, which means if we reduce LDL, we do reduce the risk of a CVD. However, it's not transpired in the current literature we have available for these PCSK9 inhibitors, Dr. Sean Kane 07:20 so I'm assuming that that's kind of the Holy Grail, if you will, for these newer agents is, you know, it's pretty clear that they improve your LDL by a lot, and we can definitely talk about by how much. Speaker 2 07:30 Yes, absolutely. And you know, a few points to consider too. You know, currently they've been studied with statins, and some patients, like pregnant patients, cannot be on statins. Patients who have extensive liver damage cannot be on statins. So if we come up with studies where PCSK9 inhibitors are approved as an alternative to statins, these patient populations can benefit out of that. Again, there are no manufacturer recommendation for mild to moderate renal or hepatic impairment and for the severe impairment, we don't have any recommendation yet, so let's take a look at some of the evidence that's out there. Total of five placebo controlled trials have been done in about 2500 patients, and what we have found is that these patients had either familial type of hyperlipidemia or were at high risk of developing an ASCVD, either a stroke or a heart attack, and they were on maximum tolerable statin dose. They had other lipid agents on board, some of them did and some of them didn't. And then PCSK9 was added on to their current existing treatment to see the reduction in LDL. What they found there was 36 to 59% more LDL reduction when PCSK9 inhibitors were added on. Dr. Sean Kane 08:47 And if you think about it, that reduction, let's say roughly around 50% is a pretty good reduction that we would see with some of our very potent statins. Given that this isn't a statin, it works differently. This was in addition to patients that were already on a statin, right? Absolutely, yes. So that's a pretty impressive LDL reduction. And like you said, the jury is still out a little bit whether we'll see the clinical efficacy or not for heart attacks and strokes, but that's super promising, that we have such a profound drop on top of statin therapy, absolutely. Speaker 2 09:18 And current literature shows that, you know, it doesn't matter what patients LDL is. We obviously want to see the decrease on it, but we want to put patient on maximally tolerated statin dose. So what we are waiting to see now is that if this additional LDL reduction is really needed, we know patients who already have previous ASCVD require a little bit more reduction in their LDL, so agents like PCSK9 can help out. But then we also have to assess the evidence for the price, whether it justifies the cost of this medication in preventing cardiovascular outcomes. Speaker 3 09:54 Because actually, as Dr. Kane you mentioned, otherwise we're just we're just chasing arbitrary numbers until we have the. Evidence that specifically says these changes matter, because once again, you know, we are in this post phase where we're no longer targeting those numbers. Of you know, thou shalt be under 70, thou shalt be under 100 and we're looking more at what are the drugs do long term. So it's, it's kind of the study came out in a tough position where obviously their research and their timing was working, working up to it, and then in the in the midst of this new information that came out in the last two years, this drug has now come out. So they're trying to rectify, how do we promote this drug based upon its LDL lowering potential, and yet still acknowledge the fact that that's not the the only piece of what would cause it to be used in practice? Speaker 2 10:37 Yeah, and once they, once they established the outcomes, the cardiovascular outcomes. I would be really interested to see what the cost benefit and cost effective analysis say, whether the cost of this medication can justify it's monoclonal antibody, and I'm assuming that it's really hard to replicate a generic product. So I mean, we're probably going to be years away from getting a generic which can help reduce the cost. Yeah, so why Dr. Sean Kane 11:00 don't you tell us about one of the trials that kind of got, probably went approved for the market in the US? Speaker 2 11:06 Rather than talking about a specific trial that was approved with I would like to talk about options one trial. It's ODYSSEY OPTIONS 1 trial. And what they try to establish over here is they try to compare other alternative add ons, or changing mild or moderate intensity statin to high intensity statin, and addition of the PCSK9 inhibitors to it. So let's break it down a little bit. This trial had 355 individuals who had LDL levels of either greater than 70 or then greater than 100, we were at high cardiovascular risk. They were already on atorvastatin 20 milligrams, or atorvastatin 40 milligrams. And they took all these patients and randomized in four different treatment groups. And so they added one treatment arm was adding alirocumab 75 milligrams every two weeks to the existing statin therapy. The second group had ezetimibe 10 milligrams daily. We do know there are some combination statin and ezetimibe products available out there, and ezetimibe can also it's a cholesterol inhibitor and can help lower the LDL, not to the great extent as the statins do. It doesn't have any long term cardiovascular morbidity, mortality established at this point. The third group is, what they did, is they took the existing statins and doubled it. So if they were in the 20 milligram group, they increased it to 40. If they were in a 40 milligram group, they increased it to 80. So again, change that to, you know, high intensity statin. And then one group was where the 40 milligram atorvastatin patients only were converted to rosuvastatin 40 milligrams, because there is that difference in LDL reduction between the two doses. And what we actually found is, if you compare to, you know, adding ezetimibe, doubling the statin dose, the atorvastatin dose, or switching to rosuvastatin, addition of alirocumab decreased the LDL the most. And this difference was clinically significant. You ask how much so in patients in atorvastatin 20 groups, the LDL levels were further reduced by 44.1% and in the atorvastatin 40 milligram patients was decreased by 54% in addition to that, Dr. Sean Kane 13:38 like we said, that LDL reduction on top of either atorvastatin 20 or 40 milligrams is roughly about 50% in terms of your LDL reduction, which is an incredible number when you really step back and think about it. Speaker 3 13:51 And one of the things I was surprised by in reading the results of this study is looking at I was actually somewhat underwhelmed by when they doubled the atorvastatin dose, for example, how little of a change you saw there, I believe a 5% reduction in LDL, if you went from atorvastatin 20 to 40, and around 4.8% from 40 to 80, yeah. Speaker 2 14:09 And then ezetimibe didn't do whole lot of difference either. I mean, there was about 20.5% reduction, further reduction in LDL, in addition to 20 milligram atorvastatin, about 22% in the atorvastatin 40 milligram Speaker 3 14:21 group, yeah. So when you compare those roles, you know, a 5% difference versus about a 50% difference. I mean that, you know, is a very nice stance for them to have for this medication. Dr. Sean Kane 14:30 Absolutely, it also really informs the dose response curve of the statin. You basically don't get much more as you start doubling the dose in terms of LDL reduction, which is different than the reduction in cardiovascular events, but still, it's a surrogate that matters in terms of how much extra oomph you get when you go with a higher dose, especially when you put that in Unknown Speaker 14:49 light of the risk for side effects. True, absolutely. Speaker 2 14:51 And you know, when they were studying this drug, they were following the ATP three guidelines. We do know that and the drug The study was published, one. As the 2013 guidelines were out there. So one of the parameters, or one of the endpoint looking at was how many of these patients were able to achieve their goals. So they did set those goals up, less than 100, less than 70. And what they found is about, you know, 84 to 87% of the patient in the alirocumab group were able to achieve their goal. LDL, per se, I just want to do, you know, make a disclaimer that we no longer follow the goals. We're looking at putting patients on optimal dose of statin Dr. Sean Kane 15:30 and, of course, and probably beyond the scope of this podcast, once you start getting these 50% on top of 50% reductions, the question of how low is too low kind of comes up. You know, it turns out that your body needs lipoproteins for a reason. You know, it's involved in cell membranes and function of a number of different body systems, and that's something that we don't really know that much about. And I'm sure that this is going to come up a lot more with these new PCSK9 inhibitors. Is we're really seeing impressive reductions, and at what point is too low for LDL as an example, Speaker 2 16:03 it's absolutely something to consider when you are practicing. You know. I really think that even though there is going to be a benefit, or there will be an established benefit in cardiovascular morbidity, mortality in future, I think this drug, with the cost and potential side effect this drug might be reserved for patients who need additional LDL lowering so they have multiple ASCVD incidences. Dr. Sean Kane 16:29 So are you officially putting your flag in the sand there, Dr. Patel, that you're predicting an improvement in cardiovascular outcomes with these new drugs? Speaker 2 16:38 I can't say anything prematurely. However, there are long term studies being done, and we're eager to see what the results will be. Speaker 3 16:45 And actually, I'd like to just touch on when I was, when I was kind of looking into this drug. Is that there's some preliminary information coming out from some of these long term studies, if I can just get to that a little bit. The One of them is the ODYSSEY ALTERNATIVE study, and this one kind of set out to answer, I believe, as we talked at the beginning of the podcast. You know, this is a medication that's approved for use in combination with the statin, but what about those individuals who can't have a statin? Is this something that can be used as an alternative and so, of course, ODYSSEY ALTERNATIVE. So they included patients at CVD risk of moderate to very high or statin intolerance, and they define that by specific muscle related adverse events at the lowest approved doses of two different statins. And they also had to have an LDL above 100 for the moderate and high CVD risk groups, or 70 as their surrogate for the very high CVD risk groups. They had a two week washout period, six weeks with fibrates. And then they did allow the use of bile acid sequestrants, niacin and fenofibrate, but not the other fibrates and the fish oil. And so they did one of the kind of a pet peeve, one of some studies is a run in phase. But in this case, it was, I think, beneficial, is they allowed this run in phase to where they were given four weeks of placebo pills and four weeks of subcutaneous injections, and then if you had any kind of muscle pain during that time period, they excluded you, because I think sometimes there's a lot of maybe generalized myalgias that come up and get reported a lot with these statins. Dr. Sean Kane 18:09 You're saying that sometimes those myalgias are unrelated to the statin therapy that the patient receives, Speaker 3 18:14 certainly, and so I think that was a very good part on the study to get rid of those individuals, just like and we talked about placebo effects and things like that. So the kind of the nocebo effect here that you know, not getting the drug, but having a myalgia, they would have attributed to a medication. So what they did is those that continued were randomized to 24 weeks of the alirocumab, 75 milligrams, subcutaneous every two weeks, and placebo po daily, or the placebo as a subcutaneous every two weeks. Plus ezetimibe 10 milligrams or placebo every two weeks, and atorvastatin 20 milligrams daily. And then at week 12, as long as the LDL was above goal, they actually increased the active drug to 150 milligrams. So the primary endpoint was again, change in LDL from baseline. And what they found, again, there's there's nothing quite published yet, but if you go into the American Heart Association, you can actually find some of the literature was presented at their their conference in 2014 at the end of the year, they found that at the end of the 24 weeks, the intention to treat analysis showed a difference between groups of the alirocumab versus ezetimibe mean of 30.4 milligrams per deciliter, Dr. Sean Kane 19:21 and that's the LDL that was reduced. Correct? Yes, yeah. And one of the things that as healthcare providers, we sometimes forget about is the accuracy and precision of, you know, a lipid panel. And one of the things to think about is that LDL, if you drew it four times on four different days for the same patient, the LDL has quite a bit of movement to it. We're really not as accurate as we'd like to be in terms of how good that number is. So kind of what you're alluding to is that difference of 30 is certainly beyond the accuracy of the test. So we can definitely detect the difference of 30, but it does come down to how clinically significant would that be, or not absolutely. Speaker 2 19:58 So I think that's a. Again, one venue where we can think that, okay, this medication can be used an alternative option to statins. But then let's look at some of the safety parameters too, right? So we mentioned this is a monoclonal antibody, and it's injected every two weeks via subcutaneous injection, so we do definitely see some injection site reaction, things like itching, swelling, pain or even bruising, has been noted in current trials, Dr. Sean Kane 20:24 and it's worth noting, this is every two week injection, so it's not like a daily injection, and certainly this is something a patient can kind of be uncomfortable with, but every two weeks is much better than every day from an adverse effect point of view, I think Speaker 3 20:36 one thing that's interesting that they did not see was a lot of neurocognitive effects. When you look at some of the data, prescribing information was point 8% with the active drug and point 7% of the placebo studies. And the reason I bring that one up is because a lot of times cognitive effects are considered to be maybe one of the byproducts of lowering the LDL too low, that those the swing of myelin sheaths within the brain that act as those insulators between neurons. If you were to lose too much LDL, you couldn't produce those and thus that would cause cognition. So it is at least encouraging to see, you know, albeit based upon short term studies, that doesn't appear to be causing that Dr. Sean Kane 21:13 some of the other adverse effects that were noted in the phase three trials included some upper respiratory tract issues like nasal pharyngitis, flu like symptoms, and again, flu like symptoms sometimes accompanied by some of the injection site reactions that we can see, then also hypersensitivity reactions. So vasculitis, which is kind of a skin rash that can be purple colored on the skin. Usually this is associated with inflammation and some inflammation of the small blood vessels. There were some patients that had hypersensitivity requiring hospitalization, but it was pretty rare. We can also see diarrhea, other GI side effects, and finally, an increase in LFTs, which is pretty common with statins. Speaker 2 21:53 Yeah, so if you're going to use this in addition to statins, you know sometimes you might have to ask patient to watch out for those jaundice-like symptoms in order to detect, you know, if there is an increase in the LFTs as well. Wanted to go back to the flu like symptoms. And one medication that comes in mind, that's weekly injection that can cause flu like symptom is like peginterferon. I think we have talked about in our previous podcast too. We don't know if the symptoms are that severe enough where you need to go ahead and recommend, you know, a Tylenol or something for like myalgia or bone aches or body aches, but we'll see the clinical use of this medication, and once it's utilized, we'll probably get to derive a recommendation as to what's the best approach, maybe just like the peginterferon, this is more of a transient issue, where patients might have more flu like symptoms in the first couple injections, they might become tolerant thereafter. Dr. Sean Kane 22:47 So as you alluded to, Dr. Patel, cost is definitely going to be one of those things that we'll have to figure out. You know, is it worth the cost or not? So right now the cost is $672 per syringe of Praluent, and that is for both the doses of the 75 and the 150. I'm sure that the manufacturer will be offering coupons and things like that, which is very common practice, maybe even drug samples, which sounds kind of goofy to me as a subcutaneous chronic injection, but you know, one or two doses to see how it affects you, I think is also reasonable, and a sample is one way to Speaker 2 23:19 accomplish that. Yeah, I think I absolutely agree with that. But usually these kind of expensive medications, they're good patient assisted programs Speaker 3 23:28 available out in the market. So I think we've kind of alluded to but the, you know, the big point of this is going to be the potential role in therapy. So, you know, Dr. Patel, where do you where do you see this being? Speaker 2 23:37 I think currently, with the evidence that we have available, it's probably going to be limited to patients who are on maximum statin dose, and yet their LDLs need further lowering. And so that's why are we going to go ahead and pick this medication? Dr. Sean Kane 23:51 The real trick for a clinician is that we don't have the clinical outcome data yet, so certainly, maximizing the statin therapy makes sense, and then after that, whether you add it or you wait for the clinical data, I think is kind of a patient specific decision that hopefully a patient and a provider can kind of sit down and talk about the risks and benefits of therapy. For me, I also see this as a potential for patients that have myopathies, regardless of what dose and what statin you pick, if you have a very high risk of cardiovascular disease. It seems like even pre clinical outcome data, you may consider this for that kind of a patient where they can't take any statin and you want to try to reduce their cardiovascular risk. But again, it's kind of that gray area, because we don't know for sure that it will improve cardiovascular outcomes. Speaker 3 24:36 Right? As I mentioned the ODYSSEY ALTERNATIVE, the final results aren't out yet, but when they release the kind of the Phase One result of it will likely show that this medication may have benefit for those individuals who can't tolerate a statin. And then to look for the future, ODYSSEY ALTERNATIVE actually has an open label extension that they mentioned that this, you know, is written in the protocol, but nothing's been released yet. But this is where the rubber is going to meet the road in terms of those long term benefits. So what they plan on doing is those individuals who are on the medication, the active drug, after 24 weeks, can then have the option of going into this extension phase, which is actually expected to last up to three years. And they're and they're doing that right now, and that is where we're going to go ahead and really see where you get those long term outcome, and so we're, you know, nowhere near this. So I think in the next couple years, we'll stay frosty for the results of this study, because this could be one that is, is ground shaking, Speaker 2 25:30 yeah, currently, I think I kind of see this in line with either ezetimibe or the bile acid resins to further lower the LDL. But I mean, if I were to compare the cost of this one to either ezetimibe or, you know, the bile acid sequestrants, I probably will go with the other two agents first. You know, obviously, like you said, Dr. Kane, I really want to respect the patient's preference, but I think they will prefer an oral agent versus an injectable. Dr. Sean Kane 25:55 Absolutely, yeah, and kind of in this, like post ezetimibe world, and I know that there was a trial published recently that showed that in the immediate post ACS setting, that ezetimibe had some efficacy with clinical outcomes. But still, I think clinicians are a little bit jaded about all of the surrogate endpoints that have been targeted for decades, and then the switch to the new guidelines and maybe not favoring some of these non statin therapies. Clinically, we're a little bit jaded about some of these, so I think it's completely reasonable to be a little critical until we get some more data. And from the drug company's point of view, it's a little tricky, because they want to get the drug to the market as soon as possible because of patent life reasons. But to show clinical benefit clinical endpoints, they need years of data to show a difference in cardiovascular endpoints. We're talking three plus years to be able to show any benefit. So there's this careful balancing act from the manufacturer of getting the drug to the market quick enough so that early adopters can start using it and paying for it, but then getting that study done by extending some of the phase three trials to be able to have enough data points to show a benefit if it does exist with, you know, stroke and heart attack and things like Speaker 2 27:05 that, absolutely and just like any other drugs that's approved by FDA and us, we know that Europe and, you know, other parts of the world have already been using these kind of drugs, and takes a little while for the FDA approval to happen. So it's worth considering data that's published, you know, in other countries, and the clinical experiences from the clinicians from those countries too. Speaker 3 27:27 Dr. Kane, it's funny you mentioned the surrogate endpoints and ezetimibe, because one of those little things that just stays in my knowledge from pharmacy school is about. You have the use of the tunica intima lining as that magical endpoint, and our drug reduces this lining, therefore our drug is wonderful, versus okay, it doesn't do anything for cardiovascular outcomes. And then you're kind of at that uh oh moment. And so I'm again, very curious to see if we, if we have that oh no kind of moment in the future. Yeah. And I'm Dr. Sean Kane 27:53 sure that the FDA had this discussion when they approved the drug, saying, again, in a post ezetimibe world should we approve it based on LDL reduction alone, or do we require the manufacturer to show a cardiovascular benefit? I don't know how that discussion went, but certainly from the manufacturer's point of view, for the reasons I said, they don't want to have that be the standard, that you can't just reduce LDL, you have to show a heart attack reduction and a stroke reduction and things like that. Speaker 2 28:18 Especially after the new guidelines, I think that will be the trend. Dr. Sean Kane 28:21 So absolutely, we see that with diabetes drugs too. Absolutely, yeah, so does it improve a 1c, yes, no, that's kind of how it gets approved, or other glycemic surrogate markers. But does that drug, in fact, improve cardiovascular outcomes and things like that? The thiazolidinediones are another issue in a post TZD world where for a while we thought they actually caused heart attacks. Given that history, it's the same principle, yeah. Speaker 2 28:47 And actually, after that huge rosiglitazone failure is when FDA started making it very mandatory for any new anti diabetic drug to prove the cardiovascular safety Dr. Sean Kane 28:59 outcomes, yeah. And again, being a little bit more cynical, it's funny that with these new diabetic drugs, instead of showing efficacy that they reduce heart attacks, they just have to prove that they don't cause heart attacks, which you'd think is kind of the opposite of what you'd want for for the drug. But again, for historical reasons, that's why they have to do Speaker 2 29:17 that, right? And sitagliptin, which is Januvia, just published a study in New England Journal of Medicine showing that sitagliptin does not increase your risk of further cardiovascular events. Dr. Sean Kane 29:28 It's like you shouldn't celebrate that, but at the same time, you really shouldn't have to celebrate that, if you know what I mean. So I want to congratulate, Speaker 3 29:35 you know, congratulations. You've essentially found that you're no worse off than doing absolutely nothing, right? Dr. Sean Kane 29:40 Interesting, okay? Well, to kind of wrap things up, you know, we focused on alirocumab or Praluent, but the other agent that was approved in August 2015 was evolocumab or Repatha. So we did focus on Praluent a little bit more, but they're both in the same drug category with very similar adverse effects and things like that, really, time is going to tell whether one agent takes off more than the other or kind of, some of the clinical nuances between the two drugs both are, again, part of this PCSK9 inhibitor that potentially could have a pretty profound, you know, role in lipid management and reduction of cardiovascular endpoints in the future. Speaker 2 30:14 Another important point to consider is it's a monoclonal antibody, which is an injectable agent. So it's injected subcutaneously every two weeks. And along with that, you should also consider cost, because currently it's labeled as 600 some dollars per injection. Speaker 3 30:32 And then lastly, as we mentioned, from the safety outcome, it does have some of the issues of, you know, potential hypersensitivity, but not quite the same, the same degree as some of the the more notable monoclonal antibodies, with with some of the tuberculosis testing, some of those things that are there, but we don't quite have this whole robust issue with resolved about how low is too low on LDL. And so as we use these, these bigger medications that produce these really big reductions, we're going to want to see and just ensure that we're not going so far, so low, that we're causing these outcomes from from not having enough of these fatty acids in the rest of your body. And of course, want to check and see if those cardiovascular outcomes are going to be better, how well improved they're going to be. Dr. Sean Kane 31:13 I have a feeling we'll be doing a podcast on PCSK9 inhibitors in the next year or two, that we'll discuss. You know, some of the results of these trials that are ongoing regarding these Unknown Speaker 31:22 endpoints. You betcha, I think we'll have to do another update. Wonderful. Dr. Sean Kane 31:26 So with that, if you haven't done so already, we love five star reviews and iTunes that helps other listeners find us in the iTunes Store. We're available at HelixTalk.com if you want to suggest any new episodes or just write us a glowing review that we can read that would be wonderful with that. I'll sign off on Dr. King. I'm Dr Speaker 2 31:43 Schumann and I'm Dr. Patel. Study hard. Narrator - Dr. Abel 31:46 Thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science. For more information about the show, please visit us at HelixTalk.com. You.