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CPD

Nonstatin Therapies and LDL-C Lowering: A Critical Analysis of the Data and Real-World Experiences

  • Authors: Christie M. Ballantyne, MD; M. John Chapman BSc (Hons), PhD, DSc, EFESC; Frederick J. Raal, MBBCh, MMed, PhD, FCP(SA), FRCPC, MRCP
  • CPD Released: 11/2/2020
  • THIS ACTIVITY HAS EXPIRED FOR CREDIT
  • Valid for credit through: 11/2/2021, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for cardiologists and primary care physicians.

The goal of this activity is to discuss the role of nonstatin therapy in the prevention and management of atherosclerotic cardiovascular disease (ASCVD).

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Benefits and limitations of ezetimibe in the management of patients with dyslipidemia
    • Benefits and limitations of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor monoclonal antibodies in the management of patients with dyslipidemia
    • Key gaps in care today with respect to the management of patients with dyslipidemia


Disclosures

WebMD Global requires each individual who is in a position to control the content of one of its educational activities to disclose any relevant financial relationships occurring within the past 12 months that could create a conflict of interest.


Moderator

  • Christie M. Ballantyne, MD

    Professor of Medicine
    Chief, Sections of Cardiology and Cardiovascular Research
    Director, Center for Cardiovascular Disease Prevention
    Baylor College of Medicine
    Houston, Texas, United States

    Disclosures

    Disclosure: Christia M. Ballantyne, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: Abbott Diagnostics; Akcea; Althera; Amarin; Amgen; Arrowhead; AstraZeneca; Corvidia; Denka Seiken; Esperion; Gilead; Janssen; Matinas BioPharma Inc.; New Amsterdam; Novartis; Novo Nordisk; Pfizer; Regeneron; Roche Diagnostic; Sanofi-Synthelabo
    Received grants for clinical research from: Abbott Diagnostic; Akcea; Amgen; Esperion; Novartis; Regeneron; Roche Diagnostic

Faculty

  • M. John Chapman BSc (Hons), PhD, DSc, FESC

    Research Professor, Sorbonne University
    Director Emeritus, INSERM
    Past President, European Atherosclerosis Society
    Endocrinology-Metabolism Division
    Pitié-Salpetriere University Hospital
    Paris, France

    Disclosures

    Disclosure: M. John Chapman, BSc (Hons), PhD, DSs, FESC, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: Akcea; Amarin; Amgen; AstraZeneca; Daiichi-Sankyo; Kowa; Novartis; Pfizer; Regeneron; Sanofi
    Served as a speaker or a member of a speakers bureau for: Amarin; Amgen; Daiichi-Sankyo; Kowa; Pfizer; Regeneron; Sanofi
    Received grants for clinical research from: CSL; Kowa; MSD; Pfizer

  • Frederick J. Raal, MBBCh, MMed, PhD, FCP(SA), FRCPC, MRCP

    Professor and Head
    Division of Endocrinology and Metabolism
    Department of Medicine
    University of the Witwatersrand
    Johannesburg, South Africa

    Disclosures

    Disclosure: Frederick J. Raal, MBBCh, MMed, PhD, FCP(SA), FRCPC, MRCP, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: Amgen; Novartis; Regeneron; Sanofi; The Medicines Company
    Served as a speaker or a member of a speakers bureau for: Amgen; Novartis; Regeneron; Sanofi; The Medicines Company
    Received grants for clinical research from: Amgen; Regeneron; Sanofi; The Medicines Company

Editor

  • Anne M. Sendaydiego, PharmD

    Medical Education Director, WebMD Global, LLC

    Disclosures

    Disclosure: Anne M. Sendaydiego, PharmD, has disclosed no relevant financial relationships.

Content Reviewer

  • Robert Morris, PharmD

    Associate Director, Accreditation and Compliance

    Disclosures

    Disclosure: Robert Morris, PharmD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: ViiV Healthcare
    Owns stock, stock options, or bonds from: GlaxoSmithKline

Peer Reviewer

This activity has been peer reviewed and the reviewer has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Abbott


Accreditation Statements

    For Physicians

  • The Faculty of Pharmaceutical Medicine of the Royal Colleges of Physicians of the United Kingdom (FPM) has reviewed and approved the content of this educational activity and allocated it 0.50 continuing professional development credits (CPD).

    Contact WebMD Global

For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]


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Follow these steps to claim a credit certificate for completing this activity:

  1. Read the information provided on the title page regarding the target audience, learning objectives, and author disclosures, read and study the activity content and then complete the post-test questions. If you earn a passing score on the post-test and we have determined based on your registration profile that you may be eligible to claim CPD credit for completing this activity, we will issue you a CPD credit certificate.
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CPD

Nonstatin Therapies and LDL-C Lowering: A Critical Analysis of the Data and Real-World Experiences

Authors: Christie M. Ballantyne, MD; M. John Chapman BSc (Hons), PhD, DSc, EFESC; Frederick J. Raal, MBBCh, MMed, PhD, FCP(SA), FRCPC, MRCPFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED FOR CREDIT

CPD Released: 11/2/2020

Valid for credit through: 11/2/2021, 11:59 PM EST

processing....

 

 

Christie Ballan...:              Hello, I'm Christie Ballantyne, Professor at the Baylor College of Medicine in Houston, Texas. Welcome to the program titled Non-statin Therapies and LDLC Lowering, a critical analysis of the data and real world experience. Joining me today are John Chapman, who is Research Professor at Sorbonne University in Paris, France. John, nice to be here with you.

John Chapman:                 It's a pleasure to participate, Christie.

Christie Ballan...:              And Derick [00:00:30] Raal, who's Professor of Medicine at the University of Witwatersrand in Johannesburg, South Africa. Derick, welcome.

Derick Raal:                       Thank you so much, Christie.

Christie Ballan...:              Well, statins are the first-line agents for the treatment of patients with dyslipidemia. They have established benefits for reducing LDL cholesterol levels and CV events. However, a considerable number of statin-treated patients do not achieve target LDL cholesterol levels in the new ESC [00:01:00] EAS guidelines or the LDL cholesterol threshold levels in the United States guidelines, even at maximally tolerated statin doses.

Christie Ballan...:              And some of them are intolerant to intensive statin therapy. These patients can benefit from the use or addition of non-statin lipid lowering therapy, which is now part of our guidelines. So in this program, we will discuss the role of non-statin therapy in the prevention and management of ASCVD. And let's start [00:01:30] off, John, let's start off about an older agent Ezetimibe and statin combination. Why is Ezetimibe an attractive agent to use in combination with statin therapy?

John Chapman:                 Well, Ezetimibe is particularly attractive, Christie, for several reasons. If we just step back and consider the possibility of attaining goal with statins, the only option we have is to double the dose until such time as we attain the LDL cholesterol [00:02:00] recommended goal. Now, the difficulty with doing that is that we do see the gradual appearance of transaminases, for example, that might be elevated, or perhaps other side effects. And equally the quantitative degree of LDL cholesterol lowering that we can attain even with the highest dose of statins may not be sufficient to reach the new lower goals, particularly in the European [00:02:30] guidelines.

John Chapman:                 Now, if we consider the possibility of combining a statin with Ezetimibe, what we must consider is that exogenous or dietary cholesterol constitutes a substantial component in contributing to the body cholesterol pool. And if we can inhibit that, we can probably reduce [inaudible 00:02:55] in that pool by something of the order of 25%, or possibly more. Ezetimibe [00:03:00] is an agent that was specifically developed to inhibit absorption of cholesterol in the intestine, and as a consequence, the transport of cholesterol from the intestine to the liver is attenuated with subsequent reduction in the dimension, the size if you will, of cholesterol pooled in the liver.

John Chapman:                 That means that as a consequence, liver LDL receptors will be [00:03:30] induced. There will be greater expression on surface, and subsequently, [inaudible 00:03:35] reduction LDL cholesterol. That results with Ezetimibe in approximately a 20% to 25% further reduction in LDL cholesterol over and above any statin dose. So it's particularly advantageous to do that. And there is substantial data in the literature that documents this major increase in LDL [00:04:00] cholesterol reduction when we add Ezetimibe at a 10-milligram dose to any dosage of any statin.

Christie Ballan...:              Well, John, that's a nice review of the physiology and the lipid effects. But what is the data in regards to randomized clinical trials in terms of cardiovascular benefit?

John Chapman:                 Well, that's a critical question, Christie, and we have essentially four major cardiovascular outcome trials that have been conducted with Ezetimibe. [00:04:30] The first one, of course, was improve it, which was a long trial, seven years, several thousand patients using Ezetimibe on the background of statin compared to placebo. They were acute coronary syndrome patients. The benefit was of the order of 17%, it was significant. And under those circumstances, one was able to attain, on [00:05:00] average, about a 50% to 60% reduction of LDL cholesterol, that is statin plus Ezetimibe.

John Chapman:                 Another trial, which is particularly relevant to our discussion is the EWTOPIA trial, which was performed in Japan, in primary prevention in patients 75 years or older. Again, this was Ezetimibe, but in this case it was monotherapy, it was compared [00:05:30] to usual care and it was an open-label study. There was no documented cardiovascular disease in these individuals in Japan for a four-year follow up. And quite remarkably, there was a 34% relative risk reduction, which was highly significant in the primary end point in the Ezetimibe group. And equally, there was a 40% reduction in the composite cardiac endpoints, and a 62% reduction [00:06:00] in coronary revascularization.

John Chapman:                 So a very convincing trial in Ezetimibe monotherapy in a primary prevention cohort in Japan. Now the third trial, which we're very familiar with, which was the pioneering trial of Ezetimibe [inaudible 00:06:16]. And this was a study of the impact of the combination of Ezetimibe and low dosing, starting 20 milligrams per day, versus a placebo of [00:06:30] statin alone. In this study in individuals with chronic kidney disease, either on dialysis or not, there was a 17% relative risk reduction in the primary endpoint, and that benefit was seen both in patients on dialysis and those who were not.

John Chapman:                 And in this instance, the average on treatment LDL cholesterol reduction was 31%. So it was particularly beneficial [00:07:00] to use that combination of Ezetimibe with some statin. The fourth and final trial is a very recent one, it's particularly important because it's in patients who have undergone a prior ischemic stroke. And this was a comparison of in fact the attainment of two LDL cholesterol targets. So in these individuals, firstly, there was a group who [00:07:30] received statin primarily, low dose with Ezetimibe, and they were called the lower target group.

John Chapman:                 And then there was a second group, which was primarily statin monotherapy. Now the higher LDL cholesterol target group was 90 to 110 milligrams per deciliter of LDL cholesterol. The lower group was less than 70 milligrams per deciliter. So [00:08:00] this corresponded to the 2016 European guidelines that the targets in those guidelines are very high risk patients. And quite remarkably, there was a 22% reduction in the lower target, while greater reduction in the primary endpoint, in the lower LVL target group versus the higher target group.

John Chapman:                 And of course that lower target group was characterized by about a 70% usage [00:08:30] of Ezetimibe plus statin in combination, whereas in the higher target group, who was very low use of Ezetimibe in combination with statin, less than 10%. So here again, in a different clinical context, we see a dramatic consequence, beneficial consequence, of the combination of Ezetimibe with statin.

Christie Ballan...:              John, the last studies were interesting. And Derick, I'd like just [00:09:00] a comment on that. It really tested a strategy, not a therapy. The strategy of going lower, primarily with combination therapy. And it's interesting, having spent most of my career working in a lipid clinic. But just a comment, Derick, you've treated a lot of difficult patients. Is this strategy of using combinations to get lower... I was very pleased to see a trial like this, and just if you could provide your thoughts on that.

Derick Raal:                       [00:09:30] I've used a lot of Ezetimibe. I think very much like we treat hypertension, we don't use a single agent anymore. And particularly with these new targets that we need to achieve, both from the European and the American side, the LDL targets are getting lower and lower. And statins are remarkable drugs. But high-intensity statin, even at the top dose, we can only really reduce LDL in the order of 50% to 55%. So adding on Ezetimibe, we can get [00:10:00] that extra 20% to 25% reduction. So I think this is going to become the standard first-line therapy for many of our patients.

Derick Raal:                       And I think, unfortunately at the moment, we often only have the combination of simvastatin and Ezetimibe. But I think what's going to become first-line are the newer atorvastatin, rosuvastatin, Ezetimibe combination as first-line therapy for many of our patients. But even with that combination, as we'll talk about, patients with severe hypertriglyceridemia, [00:10:30] for example, patients with familial hypocholesterolemia, those with established cardiovascular disease, where we've got to get to these extremely low LDL targets of 55 milligram per deciliter or so, even with a combination of Ezetimibe and high-intensity statin, we're just not going to get there.

Christie Ballan...:              John, what about the real world evidence? You've talked about RCT data. Is there any real world evidence supporting this combination approach with Ezetimibe?

John Chapman:                 Well, [00:11:00] there is, and our colleague [inaudible 00:11:02], some six or seven years ago published a retrospective study based on a managed care database in the United States. And what she did essentially was to take of the order of 15,000 patients, either with CHD or with CHP equivalent risk, all of those individuals were receiving statin monotherapy at baseline. [00:11:30] And part of those patients were subsequently treated with an Ezetimibe combination, while the other parts of the initial cohort benefited from statin titration.

John Chapman:                 And basically what Joanne showed in that study was that when she worked at the degree of goal attainment in the individuals who went on the statin/Ezetimibe combination, there was a substantially greater proportion of patients [00:12:00] in the statin/Ezetimibe combination group who attained either the less than 100 milligram per deciliter goal, or the less than 70 milligram per deciliter goal, as compared to the group receiving only statin titration.

John Chapman:                 And that was true for all the statin that she looked at, simvastatin, atorvastatin, rosuvastatin. So that managed care database, it really provides us with a nice reference, I think Christie, [00:12:30] to support the real world reality if you will, of the efficacy of the Ezetimibe/statin combination, which of course Derick has already referred to.

Christie Ballan...:              Derick, you talked about hypertension. One of the things of hypertension is we use lots of combination therapy. Well, we also have lots of combinations available. We have many different agents which are high efficacy. [00:13:00] So we talked about Ezetimibe, but what about PCSK9 inhibitors? John, you went over the mechanism of action of the Ezetimibe with a statin, what about PCSK9 inhibitors? You want to review that with us in terms of why they are additive to statins?

John Chapman:                 Well, essentially the mechanism of action of the PCSK9 inhibitors is independence, initially [00:13:30] at least, of the statin pathway, and independence of the Ezetimibe pathway. So by inhibiting PCSK9, this is another route to increase LDL receptor activity on the surface of the liver cell. And that's what PCSK9 inhibitors do, and they do it very successfully.

John Chapman:                 So that on top of statin monotherapy, we can anticipate a 50% to 60% further decrease in [00:14:00] LDL cholesterol. And a PCSK9 on top of a statin/Ezetimibe combination is going to give us another 30%, 35% of LDL cholesterol reduction. So those increments, if you will, that we can obtain with PCSK9 inhibitors in this case, Evolocumab or Alirocumab as monoclonal antibodies are very well-documented.

Christie Ballan...:              Well, John, we have also some excellent RCT data with a PCSK9 inhibitors. Can you briefly review that?

John Chapman:                 With pleasure, Christie. [00:14:30] There have been, in fact, three CVOT trials with PCSK9 inhibitors. Of course, one of those inhibitors was withdrawn, but nonetheless the trial, which was [inaudible 00:14:42] two was actually successful. I'm going to refer to the trials with Evolocumab, which was the Fourier trial and the trial with Alirocumab, obviously outcomes. So if we consider the Fourier trial with Evolocumab, first this was in patients with stable cardiovascular disease, [00:15:00] baseline LDL at 92, on-treatment LDL cholesterol with Evolocumab was 30 milligrams per deciliter.

John Chapman:                 So very importantly, that attainment, the on treatment if you will, LDL cholesterol in Fourier was not only below the new 55 milligram per deciliter goal in very high risk patients in the European guidelines, but it was equally below the recommendation in acute coronary [00:15:30] syndrome patients in those guidelines of 40 milligrams per deciliter. So I think it is quite significant. The trial was short, it was in 27,000 individuals, just over two years, 15% relative risk reduction, which was significant. And of course we can always say, "Well, if we continued the trial, would we have obtained further benefit?"

John Chapman:                 If we now consider the other [inaudible 00:15:57] outcome trial with Alirocumab, this [00:16:00] was slightly different, very similar baseline level of LDL cholesterol. But this was performed in patients presenting with an acute coronary syndrome, trial was slightly longer, almost three years, 15,000 patients. Essentially again, a 15% relative risk reduction for the composite primary cardiovascular endpoint, highly significant. But equally very interestingly, there was a [00:16:30] significant reduction of 17% in fatal events in this trial possibly because it was slightly longer than the Fourier trial, but it's perhaps a point we might come back to.

John Chapman:                 Two perhaps points to add to the Fourier and [inaudible 00:16:50] outcomes trials is that they both recorded entirely satisfactory safety profiles relative to the [00:17:00] placebo groups who received standard of care, so obviously these trials were both performed on the background of a statin treatment and that was involved in the standard of care. The other point to mention was there is now more than a five-year followup in the Oslo trial, and the safety is again entirely satisfactory in that trial for Evolocumab.

John Chapman:                 And the other point of major consideration clinically is that this is essentially the [00:17:30] complete absence of neutralizing antibodies, which are exceedingly rare in patients treated with these monoclonal antibodies to PCSK9. So I think you've got very satisfactory cardiovascular outcome data at this point, Christie. Of course, there are new trials being designed to look at earlier use, earlier introduction of these PCSK9 inhibitors, closer to events.

Christie Ballan...:              [00:18:00] Derick, so the PCSK9 story has been a very exciting one going from a family with a looked like FH, turned out to be loss of function mutation [inaudible 00:18:13], biotech. We had these drugs, they lower LDL 60%, so very impressive, but the uptake hasn't been what I thought. And come over. Can you discuss some of the challenges that have been [00:18:30] occurring in regards to that? First of all, how do you do the patient physician discussion in terms of initiation? And then why has the uptake been a bit slower than we might've expected?

Derick Raal:                       So Christie, remarkable, if it was just the science we had to rely on, remarkable drugs, the PCSK9 inhibitors. But in bold letters, unfortunately it's cost. And I think that's one of the major concerns with the use of these agents and why the uptake hasn't been as good as it should have been. We were concerned because it's given by subcutaneous injection, that [00:19:00] patients would be reluctant to take this therapy. But very similar to diabetic patients, we start on oral agents, we then have to change some of them over to injectables and they adapt very, very well.

Derick Raal:                       So I don't think the injections is a major issue with these drugs. One of the biggest problems has been the cost. And as I said, if they were as cheap as the statins we now have, as Ezetimibe, there'd be a much bigger uptake of these therapies because they are remarkably [00:19:30] effective. As John mentioned, on top of what we're using, we get another 60% reduction in LDL cholesterol. I think those are the major issues that need to be kept in the fridge, unlike small molecules you can carry around in your bag. But other than that, I think the major issue, at least for the patients I treat, has been the cost.

Christie Ballan...:              So there is some injection training that's important and there's a discussion of this with the patient, make sure they know how to do it. And I [00:20:00] think we can kind of change that because I asked in the United States, would people really care? But if the insurance covers it, they're not worried about what it cost, but it's access. Basically, the access to the drug, it's been hard to get because of the restrictions and the hoops to jump through with this.

Christie Ballan...:              So once again, hypertension, there's lots of choices, we have many different classes. There's a new agent that was recently approved by the US food and drug administration [00:20:30] and the EMA, Bempedoic acid for patients with [inaudible 00:20:33], FH or established ASCBD who need additional LDL cholesterol lowering. Can you tell us more about that, Derick? Where do we stand in regards to mechanism of action and what's the trial data?

Derick Raal:                       Sure. So Bempedoic acid is an interesting drug. It inhibits ATP citrate [inaudible 00:20:52], which is an enzyme just upstream from HMG-CoA reductase. So in other words, it works on the same pathway [00:21:00] as statins, but just proximal to that. And then by the same mechanism of action, it will increase LDL receptor numbers. Interestingly, it's a prodrug, so it has to be activated in the liver. So one benefit of Bempedoic acid compared to the statins is the less muscle side effects because statins are active both in muscle as well as in the liver.

Derick Raal:                       So there's been a big program, the CLEAR program with the use of Bempedoic acid, I think it's over 4,000 [00:21:30] patients have been rolled into the CLEAR up program, and it's an effective drug. So on top of statin therapy, and if you add it to Ezetimibe, you'd get a further reduction in LDL cholesterol with this oral agent. Unfortunately, it's not as potent as we see with the PCSK9 inhibitors, for example. So the average reduction is probably similar to Ezetimibe in the order of 15% to 20%.

Derick Raal:                       In the studies [00:22:00] to date, there have been some side effects from the medication that does increase uric acid. There hasn't been an outcome study yet to show reduction in mortality, but the genetic data looking at the pathway would suggest it's going to be effective. So I think it's an added agent that we can add as combination therapy for our patients. It will be statin, Ezetimibe, possibly Bempedoic acid. And then [00:22:30] for the ones we're really struggling to get at, we need to look at drugs like the PCSK9 inhibitors.

Christie Ballan...:              Well, I was talking about biotechnology and PCSK9 inhibitors, and to be honest with you, Derick, when they first said an injectable monoclonal antibody, I thought, well, where is that? It seemed a little bit far-fetched to me, certainly I've used it with cancer or other types of things, but the data has been quite impressive. Now we've gone to another uneven [00:23:00] additional step with biotechnology and it's back to PCSK9. Can you tell us about Inclisiran? This is being reviewed, I know, by the food and drug administration, but it's really quite an interesting agent in terms of its mechanism of action. What's the data in regards to this agent?

Derick Raal:                       So this is a very exciting drug and I think it's going to be very disruptive in terms of the way we manage hypercholesterolemia. So the PCSK9 inhibitor, the [00:23:30] monoclonal antibodies act by mopping up PCSK9 from the circulation. And for that reason, they have to be given every two weeks or the bigger dose every month. So some bright chaps said, "Well, instead of trying to mop up PCSK9, let's and turn off the production of PCSK9 by the liver." And the way that is done, it says, quote, "Small interfering RNA. There's a little double standard RNA that is taken up by the liver, it's directed [00:24:00] towards the liver by [inaudible 00:24:01], taken up by the liver.

Derick Raal:                       And it turns off the manufacture or the production of PCSK9 by the liver. The difference between the monoclonal antibodies and Inclisiran is that it recirculates within the hepatocytes." So there's a thing called a risk complex, and RNA juice complex. And the Inclisiran keeps recirculating within this complex. So unlike the monoclonal antibodies, [00:24:30] Inclisiran can be given once every six months. So it's very much like a vaccine for the flu, we can give Inclisiran to patients twice a year, and it would reduce LDL cholesterol, on top of current therapy, by the order of 50%. So the big outcome studies, the phase three studies, with Inclisiran that have been done, have shown an average reduction of about 50% in LDL cholesterol.

Christie Ballan...:              So, and [00:25:00] then Derick, you mentioned these studies. Do we have even trials yet, or were those lipid trials? And what was the magnitude of those studies?

Derick Raal:                       So these were the phase three trial, so it's called the ORION program. And the main ones that were done was the ORION-9 study in patients with [inaudible 00:25:17] hypercholesterolemia, just under 500 patients. The other two large studies were ORION-10 and ORION-11, and those were patients with established at-risk cardiovascular disease or very high [00:25:30] risk. They were about 1,500 patients in each of those studies. So the total patient pool was just over 3,000 patients. And as I said, this was really looking at the efficacy and the safety of Inclisiran. And if you combine all those three studies, the average reduction in LDL was about 50%.

Derick Raal:                       Safety-wise, also remarkable except for the odd injection site reaction, which we also see with the monoclonal antibodies, a remarkable [00:26:00] drug, but we do not yet have a big outcome study. One is planned, in fact, it's busy enrolling at the moment. They're using the Oxford site and the [inaudible 00:26:10] site, and that's going to be a large outcome study over 15,000 patients, looking to see whether Inclisiran will also reduce cardiovascular events. But I would say probably very similar if you believe in LDL cholesterol as the cause of atherosclerosis, I would expect that the study is going [00:26:30] to be positive as we've seen with Odyssey outcomes in the Fourier study.

Christie Ballan...:              So in addition to the [inaudible 00:26:36] from the phase three lipid programs, I understand there's also a large extension of those programs that's ongoing, and we have an outcomes trial that's in progress where a DSMB meets on a regular basis. So in addition to the published data, there's quite a bit of other safety data that's been accumulated. Is that correct there?

Derick Raal:                       That's correct. So, the follow up of the three phase three [00:27:00] studies is called ORION-8. And that's really looking at long-term safety and confirming that the efficacy is maintained in the longterm. But the real big study code, ORION-4, is going to be the cardiovascular outcome studies, which will only really read out in probably three years or so. But remarkably effective therapy.

Derick Raal:                       And as I said, it's going to change the way we think, because we may turn things around. We want a 50% reduction in LDL cholesterol, which you can get with [00:27:30] Inclisiran. So you give that to your patients in injection twice a year. If you're not attaining goal, we will then add the other therapies to it. So it may actually turn things upside down in terms of the way we think about managing hypercholesterolemia.

Christie Ballan...:              Okay, well so I think if we go back to this concept that you brought up about hypertension, there was another survey recently, the DaVinci study that Coach Ray presented at the ESC meeting, [00:28:00] about 6,000 people mixture of primary prevention and secondary prevention. But once again, it turns out that if you look at what patients are doing, not what the guidelines say, and what's happening in practice, moderate intensity was 52%. High intensity, 38%. Ezetimibe, 9%. PCSK9 inhibitors were less than 1%.

Christie Ballan...:              And we've looked at registries in the United States, with a [inaudible 00:28:29] registry, but [00:28:30] you'll see that 70% of patients are on combination therapy for hypertension. And yet, we have these very low numbers in regards to treating lipids. And I guess this is a thing, Derick, you mentioned you think that this is going to be changing for it. And if we look at the field of hypertension... I mean, [00:29:00] I've been around for a while, and when I was an intern we had hypertension, we used one drug, we'd go to the top dose, and then we'd go to the next drug. So why did we change in hypertension? And why have we not changed in lipids?

Derick Raal:                       It's really strange, it's a good point. One of the concerns, if we over treat hypertension, we get the blood pressure too low and you get side effects. But that hasn't been shown with LDL cholesterol reduction. I don't think there's a lower limit, in terms [00:29:30] of safety at least. The lower the better, but to try and change the prescription, one of our problems still is we sort of start with one drug, we add a second, but I think we need to change the mindset of physicians.

Derick Raal:                       They've got to think, particularly in patients that are extremely high risk and those with severe hypercholesterolemia, about coming on board with combination therapy right at the onset, because that's your first meeting with a patient. You say, "All right, I really want to get your [00:30:00] LDL cholesterol down. You've had a stent, you've had a [inaudible 00:30:03] function. I'm going to get you as low as possible, I'm starting you on a decent dose of a statin. And I'm adding other agents to really get that LDL cholesterol down."

Christie Ballan...:              So that's why it's interesting because when you work in a lipid clinic, and you see somebody who didn't know they had FH and they haven't had an event or something and their LDL is 300. Well, [00:30:30] it's routine for 20 years to be using combination therapy from the start. So I think the issue that does come up is, I think there was a certain pragmatism in hypertension where people realize, listen, we're going to be more effective if we go to combination therapy much earlier.

Christie Ballan...:              And then the guidelines change. And I guess part of it was, we didn't have the data on the non-statin therapies in advanced until recently as reviewed by John. The Ezetimibe [00:31:00] trials were somewhat later and the PCSK9 trials. John, what are your thoughts about this? We've all been watching this field. What do you see happening now on practice and what do you foresee things moving?

John Chapman:                 Well, Christie, this is a very interesting discussion. If I could just refer back to the comments I made on the [inaudible 00:31:24] trial, I quoted a couple of incorrect results there. The actual [00:31:30] LDL cholesterol reduction in the intervention [inaudible 00:31:33] with Ezetimibe was 24% and that gave a relative risk reduction of just over 7%. I actually quoted it's 15%. So do excuse me, but we need to correct that. Now coming back to your key question.

John Chapman:                 I think we all agree here that we've lagged behind in going to combination treatment [00:32:00] in the lipid field, with the exception if you'll both agree, of lipid clinics, where we have far more specialized clinicians, clearly higher risk patients. And it may be the fact that dyslipidemia patients are seen by numerous clinical specialists, that is to say, all the way from rheumatologists and nephrologists, and so on and so [00:32:30] forth.

John Chapman:                 Whereas, I hate to use the expression hypertension docs, but in internal medicine and certainly in Europe, there are individuals specifically in those departments to a much lesser degree in cardiology and endocrinology. So it may be that the greater clinical specialization and knowledge of hypertension and the earlier appearance of combination agents and mechanisms, facilitated [00:33:00] or encouraged the earlier use, the earlier advent if you will, of combination treatments in that field. It's just a suggestion. And obviously your comments, Derick and Christie, are paramount here.

Christie Ballan...:              So I think if we kind of put this in perspective, basically some of our older agents, John, they were difficult to use. Niacin was not a patient-friendly drug. You had to use very high dosages, body resins, Derick. I mean our patient [00:33:30] struggled with these, but now we have Ezetimibe, we have a new oral agent. I mean, the injections, as you point out Derick, are easy. And then we have in the pipeline, something every six months. So it's a very different world.

Christie Ballan...:              And we have the evidence from the non-statin trials, once again, refocusing as that really it's the LDL cholesterol achieved which is the critical issue in regards to events. And I'm [00:34:00] going to finish up Derick, I think for me, the biggest challenge as a clinician with my patients is adherence to lifestyle. So diet and exercise, and we see this, it's a real challenge, and also taking the medications. And you mentioned that Inclisiran could be a paradigm changing or disruptive technology. But every six months, that's a little different. And just maybe your thoughts about where [00:34:30] this might end up going for us.

Derick Raal:                       So Christie, you're right. We now have the tools, we have remarkable new drugs for treating hypercholesterolemia. And combination therapy, I think, is going to be the way forward. But as you say, first-line it's about patients, are they accepting to taking multiple drugs? We've got to educate them on diet and exercise. We tend to forget about the things, patients say, "Well, now I'm on a tablet, an injection. I can do what I want," but I think important [00:35:00] is both physician factors and patient factors. And I think if we can encourage more use of combination therapy, will definitely benefit our patients.

Christie Ballan...:              Well, John and Derick, thank you for this great discussion. Derick, you talked about disruptive... My dream is that we could have a prevention visit. They get their injections, so they've knocked their cholesterol down for six months. And then we also focus on diet, exercise, blood pressure control, weight loss, diabetes. But it would be all focused on prevention. [00:35:30] Anyway, that's a hope for the future. We'll see what happens. I want to thank the audience and thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

 

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