Transcript Details This is a transcript of a continuing medical education (CME) activity accessible on the ReachMD network. Additional media formats for the activity and full activity details (including sponsor and supporter, disclosures, and instructions for claiming credit) are available by visiting: https://reachmd.com/programs/cme/cardiovascular-controversies-emerging-therapies-loweringcardiovascular-risk/7451/ Released: 05/01/2015 Valid until: 04/30/2016 Time needed to complete: 15 minutes ReachMD www.reachmd.com info@reachmd.com (866) 423-7849 Cardiovascular Controversies: Emerging Therapies for Lowering Cardiovascular Risk ReachMD Announcer: Welcome to CME on ReachMD. This segment, Cardiovascular Controversies: Emerging Therapies for Lowering Cardiovascular Risk is sponsored by the New Jersey Academy of Family Physicians and supported by an educational grant from Pfizer, Amgen, Sanofi-Aventis, U.S. and Regeneron Pharmaceuticals This segment will focus on new emerging research and mechanisms of action for lipid lowering therapies, including PCSK9 inhibition. The target audience for this educational activity includes primary care providers, and other clinicians who treat lipid-related disorders. This activity is approved for.25 Prescribed credits by the American Academy of Family. This activity is approved for.25 AMA PRA Category 1 Credits by the Texas Academy of Family Physicians. Your moderator is Dr. Brian McDonough who will be speaking with Dr. Carl Orringer, Associate 2018 ReachMD Page 1 of 7
Professor of Medicine in the area of Clinical Lipidology and Director of Preventive Cardiovascular Medicine at the University of Miami. Both Dr. McDonough and Dr. Orringer have indicated that they have nothing to disclose. After listening to this activity, participants should be able to discuss new emerging research and mechanisms of action for lipid lowering therapies, including PCSK9 inhibition. Statins have shown efficacy in lowering LDL-C and in reducing cardiovascular events; however, there are patients for whom statins produce an insufficient response and those who cannot tolerate statin therapy due to side effects. In addition, there are negative cardiovascular consequences for having abnormal levels of other blood lipids. There are a number of agents that are newly approved or in late stage development that are attempting to address these issues. Today, Dr. Carl Orringer will discuss these agents. Dr. Orringer, first of all, welcome to the program. Thank you very much. My first question for you Carl is, why is the development of new lipid lowering therapies important in today s world? Well, based on the 2013 American College of Cardiology/American Heart Association Guideline on the treatment of blood cholesterol as well as on the National Lipid Association recommendations for the patient-centered management of dyslipidemia, moderate intensity statin therapy is defined as that therapy that results in a 30 to less than 50% reduction in LDL cholesterol, and a high intensity statin as that resulting in a greater than or equal to 50% reduction. Now the cholesterol treatment trialists metaanalysis of statin trials showed that each 39 mg/dl reduction in LDL cholesterol is associated with an approximate reduction in major atherosclerotic cardiovascular disease events of about 20%. Therefore, if we assume that a moderate intensity statin reduces the patient s baseline LDL cholesterol from 180 to 102 mg/dl that patient s risk would be lowered by 40%, still leaving a lot of room for residual risk reduction strategies. Now, some of the residual risk is related to modifiable risk factors that include lifestyle changes, but some is related to lipid abnormalities aside from LDL cholesterol. Also, there are patients who, for a variety of reasons, do not achieve optimal levels of LDL cholesterol using statins. We need agents that address lipid and lipoprotein abnormalities other than abnormal 2018 ReachMD Page 2 of 7
LDL cholesterol levels and agents that can help lower LDL cholesterol in patients who can t tolerate statins or for whom statins are not enough. Let s switch for a moment to HDL cholesterol. How does raising HDL cholesterol lower cardiovascular risk? Numerous studies have shown that a low level of HDL cholesterol is a major independent risk factor for atherosclerotic cardiovascular disease. Our understanding of HDL structure and function is evolving. We know that HDL particles carry a varied cargo, including a varying number of Apo A1 protein molecules, other Apo lipoproteins, cellular lipid transporters, enzymes, cholesterol and triglycerides. Now HDL particles have a number of effects that reduce atherosclerosis, including anti-inflammatory, antioxidants, antithrombotic and antiapoptotic properties. However, the major function is clearance of cholesterol esters. This occurs through 2 mechanisms, the first is direct uptake by the liver or tissues that produce steroids or transfer of cholesterol esters to Apo B-containing lipoproteins in exchange for triglycerides which is mediated by cholesterol ester-transfer protein. Now, recent research on the relationship between cardiovascular risk reduction and HDL is focusing on the quality of the HDL particle, particularly, the cholesterol efflux capacity. The National Lipid Association recommendations for the patient-centered management of dyslipidemia, recognizes HDL cholesterol as an important risk marker, but not a target of therapy, since HDL cholesterol-raising strategies have thus far not been of demonstrated benefit in atherosclerotic cardiovascular disease risk reduction. However, drugs in development are examining whether approaches that both raise HDL cholesterol and lower LDL cholesterol are associated with improved patient outcomes. Now I want to know what agents are in Phase III development that lower LDL cholesterol levels while raising the HDL cholesterol levels as you alluded? Well, 2 CETP inhibitors currently in clinical trials lower LDL cholesterol and raise HDL cholesterol, one is anacetrapib, which is an orally active, selective CETP inhibitor. The DEFINE study enrolled subjects taking a statin and at National Cholesterol Education Program, Adult Treatment panel III, LDL cholesterol goal and randomized these patients to receive anacetrapib or placebo. Now anacetrapib raised HDL cholesterol by 138% and decreased LDL cholesterol by 40% after 24 weeks of therapy and safety and tolerability were maintained at 76 weeks. These results continued in the 2 year extension study. Also, evacetrapib, is also a selective CETP inhibitor and when combined with statin therapy has 2018 ReachMD Page 3 of 7
demonstrated an 80 to 94% increase in HDL cholesterol and a 46 to 52% decrease in LDL cholesterol. On February 19, 2015, the manufacturer extended the ACCELERATE Phase III trial for an additional 6 months to examine whether the use of evacetrapib with statins would reduce major cardiovascular events compared to the use of statins alone in patients with atherosclerotic cardiovascular disease. Interesting. Let s shift now to triglycerides. Does lowering triglycerides improve cardiovascular risk? Well, epidemiologic and genetic studies have shown that hypertriglyceridemia is associated with increased atherosclerotic cardiovascular disease risk. This is most likely related to the presence of increased concentrations of small LDL particles and a concomitant increase in the concentration of cholesterol carrying triglyceride remnant particles. When triglyceride concentrations are greater than or equal to 500 mg/dl the focus should be on triglyceride lowering to reduce the risk for pancreatitis. With lesser triglyceride elevations, the risk is primarily related to atherosclerotic cardiovascular disease. Lifestyle approaches with reduction in saturated fat and simple carbohydrate intake, along with cardiorespiratory exercises is recommended for most patients. But those who don t respond to these measures are those with marked triglyceride elevations, are candidates for drug therapy. Fibrates, omega-3 fatty acids, and/or niacin may be used for the treatment of triglyceride elevations greater than or equal to 1000 mg/dl. For diet-resistant hypertriglyceridemia with levels of 500 to 999 mg/dl in the absence of a history of pancreatitis, statins may be used as first-line therapy as they will lower triglycerides and also reduce cardiovascular risk. There are no large scale randomized trials investigating whether lowering triglycerides reduces cardiovascular disease, but there is evidence for metaanalyses and from post-hoc analyses of trials of triglyceride lowering therapy using fibrates and/or niacin, the cardiac events were lowered as well. Are there any new agents to help lower triglyceride levels? Well, there are 2 agents that have been approved for the treatment of homozygous familial hypercholesterolemia. One is called lomitapide which is a microsomal triglyceride transfer protein inhibitor that lowers LDL cholesterol and also, coincidentally, lowers triglycerides. Similarly, another agent called mipomersen which is approved also for homozygous familial hypercholesterolemia has been shown to cause significant reductions in triglycerides. However, it is important to point out that neither of these drugs are available for routine use for triglyceride elevations and should be limited only 2018 ReachMD Page 4 of 7
to the use in patients with the diagnosis of homozygous familial hypercholesterolemia. That s interesting, so when you are looking at those things, you obviously, have to look at whether you are treating patients with certain conditions and evaluating. That s again, where the patient history is so important. If you are just tuning in, you are listening to CME on ReachMD. I am your host, Dr. Brian McDonough, and today I am speaking with Dr. Carl Orringer. I want to shift for a moment to the PCSK9 inhibitors, agents in development for lowering LDL cholesterol. The next question and it s an obvious one, what is PCSK9? Well, PCSK9, and this has a long name, which is proprotein convertase subtilisin/kexin type 9. You don t have to remember that; I am not going to test you on that one. But it is made by hepatocytes and it helps to regular cholesterol homeostasis by breaking down LDL receptors. PCSK9 bonds to the LDL receptor on the surface of hepatocytes and this causes the receptor protein complex to be internalized into the cell and then broken down. Studies have shown that because statins deplete cholesterol content in the liver they lead to an upregulation of LDL receptors and of PCSK9. There are a number of agents under investigation for inhibiting PCSK9 including monoclonal antibodies, antisense oligonucleotides, small interfering RNAs and other small molecules. The monoclonal antibodies are in Phase III clinical trials. I am sure we have a lot of listeners who are saying it is tough enough to remember PCSK9, but it is a lot easier than remembering what it really stands for, so I agree with you with that, Dr. Orringer, but now that we are looking at this, and we are looking at this important group of medications, what have the trials of monoclonal antibodies against PCSK9 found? Well, there have been some very exciting trials that actually were presented at the American College of Cardiology meeting in San Diego. Two such agents are actually quite far along in their development, one is called evolucumab, and this drug is a subcutaneously administered monoclonal antibody to PCSK9 and it has been studied in 6 Phase III trials. It has been studied as monotherapy and in combination therapy with statins and with ezetimibe in patients with and without heterozygous familial hypercholesterolemia. At all trials, a significantly lowered LDL cholesterol compared to control groups with an acceptable safety and tolerability profile. And a study that was published in the New England Journal of Medicine just this past week, on March 17, 2015, showed that the administration of 2018 ReachMD Page 5 of 7
this drug resulted in a 61% reduction in LDL cholesterol on top of that which was achieved by statins. And now we are looking at longer term trials to document not only that it is effective at lowering LDL cholesterol but it is effective in reducing cardiovascular events. Another PCSK9 inhibitor called alirocumab is also being studied and was also discussed at the American College of Cardiology meeting, as was an article published on this drug in the New England Journal of Medicine on 3/17/2015, looking at its efficacy and safety in reducing lipids and, to some extent, its ability to reduce cardiovascular events. This also is a subcutaneously administered drug that lowers LDL cholesterol by more than 60% and seems to be very well tolerated in those populations that have been studied. So, we are now looking at a new era in which patients who are taking statins who need even greater LDL cholesterol reduction, or who cannot tolerate statins, might have an option for therapy that causes dramatic reductions in LDL cholesterol, and the early signals are, that these drugs are safe and that they will likely reduce cardiovascular events--but long term trials and longer term followup is clearly needed for evaluation of the clinical safety and utility of these drugs. These are very exciting times, aren t they? Well, they really are, you know, we are now looking at times when we can literately drastically slow down, and in many cases, stop the process of progressive atherosclerosis. We now know that marked reductions in LDL cholesterol using statins can definitely alter the natural history of coronary artery disease. We recently found out that the addition of ezetimibe, the cholesterol absorption inhibitor, to statin therapy in patients whose LDL cholesterols were less than 70 also reduced events and now we are looking at an entirely new way of lowering LDL cholesterol using drugs like evolucumab, alirocumab and even a third drug, bococizumab, which is also a monoclonal antibody to PCSK9. All of these drugs now are being examined and we are looking with great interest as to whether these dramatic reductions in LDL cholesterol will be associated with a marked reduction in atherosclerotic cardiovascular disease events and do it in a safe fashion. We only have about a minute left, but I wanted to ask you about that, you know, the excitement of what s going on, on the heels of JNC-8and the meetings they had with the ACC, with all the changes and new ways of looking at things, are you optimistic we are even going to do a better job going forward with cardiovascular disease? 2018 ReachMD Page 6 of 7
I am extremely optimistic. I think that probably the greatest thing that is happening is that there is active and carefully performed trials that are actually answering clinically important questions. We are entering an era where we recognize that, although we have better treatments for patients who develop complications of atherosclerotic cardiovascular disease, we recognize the importance of prevention and prevention is the key aspect of primary care physicians. Strong preventive measures can make a huge difference, keeping our patients out of the hospital, reducing their healthcare costs and approving their quality of life. And so, these kinds of treatments are approaches that we are looking forward to moving to the primary care arena so that fewer patients have to go to the specialists for either surgical or interventional procedures. I want to thank our guest, Dr. Carl Orringer, for helping us better understand familial hypercholesterolemia, statin intolerance and talking about some of these major new and exciting developments. Thank you again, Dr. Orringer. Thanks very much Brian. ReachMD Announcer: This segment of CME on ReachMD is sponsored by the New Jersey Academy of Family Physicians and supported by an educational grant from Pfizer, Amgen, Sanofi-Aventis, U.S. and Regeneron Pharmaceuticals. To receive your free CME credit or to download this segment, go to ReachMD.com/CME online or your Smartphone device. Thank you for listening. 2018 ReachMD Page 7 of 7