Dean Karalis, MD

 What’s really important—and we’re not here to give advice to the manufacturer of inclisiran—is the reputation a drug develops when it’s brought to the marketplace. It sticks. To Dean’s point, if you look at data published by Seth Baum and others, they found that the utilization of PCSK9 was somewhere about 0.3% of those who were eligible.

What happened was you had the insurance payers creating these incredible speed bumps. It didn’t really matter. The manufacturers of PCSK9 inhibitors cut their price in half. As Dean, Manesh, and Linda have said, the access to the PCSK9 inhibitors has certainly become easier. But the doctors just aren’t interested in prescribing. As far as they’re concerned, it’s a drug that’s very difficult for patients to access. It’s an “expensive” drug. I urge the manufacturer of inclisiran to think the process through, so that when this drug finally comes to market, it is accessible. 

Otherwise, you’re going to have the same issues that we face with PCSK9 inhibitors. Perhaps we need to inject some artificial intelligence into value-based care instead of what seems to be artificial insanity. We need to be able to count on really good algorithms to determine appropriate use for these compounds.

I still have heterozygotes being turned down for PCSK9 inhibitors. It’s insanity out there. What we really need is really good artificial intelligence, not artificial insanity, in terms of making sure these drugs are being used in the appropriate patient at the appropriate time.

 Norman, that was a wonderful take-home message. In fact, I’m going to start with Dean, Manesh, and Linda; you’ll be last. Give me a similar take-home message, something you think our audience needs to hear from you. Dean?

 In secondary prevention, the LDL [low-density lipoprotein] goal is less than 70 mg/dL and probably lower for all our patients. That’s going to require combination therapy, the best statin dose you can get them on, and then other drugs.

If the cost of the medicine is too expensive, then use ezetimibe. For primary prevention, family history, pay attention to risk-enhancing factors in the guidelines and calcium scoring. That’s how we can get these patients treated earlier, so we’re not in the situation where they’ve already had events and you’ve got to be that much more intensive with regard to their treatment.

 We’re at the age where we have an explosion of possible therapies for our patients, which is great. The take-home message for me is this isn’t about cardiology or specialty care; it’s about primary care. This is about getting the message and the care pattern and the access to the primary care. That’s how we’re going to affect the population health, by getting these therapies—statin, inclisiran if it comes on the market, PCSK9 as we’ve just heard—into the hands of our primary care doctors and getting them comfortable with having the conversation with patients to get the therapies to them.

 That’s a great comment. Linda, you have the last take-home.

I just want to reemphasize lifestyle. Diet is absolutely critical. You can have somebody who is not at goal and they’re eating a terrible diet, and they can have really good results from changing that diet. Using our licensed nutrition folks and getting these people to improve their diet is very much a part of the picture.

 Thank you very much. I’m Dr Keith Ferdinand for HCPLive®. We’ve had a rich and informative discussion. Linda, Dean, Norm, and Manesh have given us a wealth of ideas and information, reviewed data, and given some opinions on where we are now with the intent of lowering risk in patients who are high risk, including the FH [familial hypercholesterolemia] patients, patients with ASCVD [atherosclerotic cardiovascular disease].

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Final thoughts from expert KOLs regarding treatment decisions and how they relate to patient accessibility when manage dyslipidemia. 

Treatment Decisions and its Relation to Patient Accessibility  

Linda, I’m going to ask you about value-based care and how that will affect our use of agents going forward. It’s a concept, but I don’t know how it’s been manifested thus far throughout the country. I don’t really feel that in my practice in New Orleans. But before we do that, let me make 1 point. Even if we have value-based care, we’re going to have to talk to our patients and do what’s called shared decision-making. The days are gone where we could scribble in our bad handwriting something on a prescription pad and say, “Take this to the pharmacy. This is your drug. I want you to take it.” 

We have to discuss with patients the medication, the indication, and some of the potential adverse effects. How bad are those adverse effects? Are they intolerable? Are they going to be short-lived? Is this something I really need to do, Doc? If we don’t do that, they’re going to take their prescription. They’re going to smile and never take the medication or stop—about half of them—with statins after 1 year.

That’s my take on shared decision-making. We’ve got to do it. Patients demand it. They’re going to get information from other sources or, even worse, misinformation. Linda, value-based care: Is it a reality? Should we be concerned? How is that going to affect our treatment of high-risk patients with hypercholesterolemia?

You nailed it, Keith. The clinician-patient discussion is critical, having the patient understand how important this is to their future health. Honestly, the makers of the monoclonal antibody inhibitors of PCSK9 have had wonderful programs to support our Medicare. The whole cost thing is mainly in the Medicare population.

In the ideal scenario, both companies making the monoclonal antibodies have a support program and the medication is provided for free. I really have to give them kudos for doing that.

 But I think you will agree that inclisiran is investigational. But if it comes on the market and does not take into account access issues and affordability issues, it’s going to have the same problem that the PCSK9 inhibitors had early on, the problem of uptake and actual use. Regardless of how great the studies are that Norman Lepor has done with this particular agent, how good is an agent if it’s not going to be used? Would you agree with that?

 I was going to share that in the value-based world, we have gone through a few pilot programs—we call them these bundle payment care initiatives with the Medicare group. We agree on a price for a patient from PCI [percutaneous coronary intervention] to 90 days, or bypass to 90 days. More of these things are going to be coming.

If we could figure out a way to really engage that process—if I’ve taken the time to put a several-thousand-dollar stent in, or a procedure in a patient who’s had a heart attack, if I could inject that patient on the catheterization lab or make sure they got an injection before they left, whether it was every 2 weeks or every 6 months—that would certainly change the care paradigm and probably would become a way in which we would demonstrate effectiveness for that patient.

Those are going to be places in secondary prevention where we have opportunities—at the time of events, before we get them to clinic or right after, when we get them to clinic and we’re through cardiac rehab—and we’ll demonstrate some of the best value.

Yeah, value-based care is here and it’s going to become even more common in our practices. As Manesh said, we’re already working with bundle payments. As physicians we’re being graded on the quality of care, blood pressure control, lipid control, etc. So it’s here.

Most physicians and clinicians know the guidelines. The question is, how do we translate those guidelines and implement them in real-world practice? That’s the challenge we all face. Some of that answer is in technology. We’ve got to be careful how we use it with our electronic medical records but prompts and cues in the electronic medical record address physicians’ issues but also patient issues. That’s where the technology can help, addressing both physicians’ issues and patient issues.

Linda said it: Right now, most patients with commercial insurance can get a PCSK9 inhibitor without much of a preauthorization process. Yet we’re still underutilizing them in real-world clinical practice. Can we use prompts or cues? Can we use technology to help physicians recognize when they should be using these agents? Then we use that same technology to help educate and move the discussion with the patient about why physicians are choosing these medications.

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Importance of shared decision making and value-based care when making treatment decisions for cardiovascular patients. 

Shared Decision Making and Value-Based Care 

 Linda, we did talk about 1 agent. We’ve covered a wide range of investigational agents. We went back to statins and we got from Dean a good look at how important they are as the bedrock for intensive lipid lowering. Bempedoic acid. I’m not going to use the words statin intolerance, and the FDA doesn’t really utilize that term. Let’s say patients say they have statin-associated adverse effects, which they don’t accept. They feel they can’t take a statin. I’m not debating whether it’s true statin intolerance. Is bempedoic acid with or without ezetimibe another additional agent that may be beneficial for those patients?

Yes. Actually, bempedoic acid is better used without a statin because, of course, the 2 agents work on the same synthetic pathway of cholesterol. When you add bempedoic acid to a statin, you get only 18% to 19% LDL [low-density lipoprotein] reduction. When you use it without statin, you get a 28% reduction. That is a reasonable reduction in LDL. And if you use it with Zetia, you get a 38% reduction. You’re getting a real LDL reduction with the combo medication.

Some adverse effects are listed in the package insert, and you can tell me whether you’ve seen them manifested in clinical practice. That also goes to Norm, Manesh, and Dean. They mention elevation of uric acid, and they also mention tendon rupture. When you think about those findings, it comes out of the clinical trials in terms of the ability to use bempedoic acid more widely.

 I do not use it in patients with gout. I have not. I’m not sure what to make of the tendon rupture. I would be interested to hear what other people say.

Anyone else wants to jump in? Bempedoic acid. We’ve already heard about the uric acid. What about the tendon ruptures? Is that a real concern? It’s in the package insert.

Yeah, the tendon ruptures are interesting. If you look at the trials given to the FDA for approval for bempedoic acid, there was a small increase in tendon rupture. When they pooled the data from all 4 trials, looking at clinical and efficacy, that signal of tendon rupture was not there. It’s unclear whether that really is a true adverse effect related to bempedoic acid.

Plus, we also know that patients, especially those with FH [familial hypercholesterolemia], once they are treated and their LDL cholesterol is lowered, they’re at risk of tendon rupture. Is a little bit of it an adverse effect from the medication? Is it related to lowering the LDL cholesterol? The issue with gout is probably real. We do see increased levels of uric acid, and there is an increased risk of gout in patients, especially with a history of gout.

But the indication for bempedoic acid is similar to PCSK9 inhibitors. It’s patients with FH and patients who have clinical ASCVD [atherosclerotic cardiovascular disease]. So you’re weighing the risk of a potential gout episode over the hope of lowering LDL cholesterol and preventing a major cardiovascular event.

I agree. I have not used it in people with gout because of the concern and potential other agents. The tendon rupture and the small signal are hard to make. The FDA put it in there because they’ve got other therapeutics. When those are widely used, tendon ruptures have become issues. There are antibiotics in other examples. Even a small signal for the regulatory agency makes it really hard for them not to do it.

As a clinician, I have no idea who is at risk for a tendon rupture outside the FH population, so I don’t know what to make of it except that I avoid it in patients with gout.

 We’re looking at it closely because I’m the PI [principal investigator] with this trial, CLEAR Outcomes, so I know we’re looking close at this complication. It’s to the point that if you have a patient who has experienced a tendon-like situation, there’s a lot of information you’re going to have to obtain on that patient in the clinical trial. Perhaps it’s from internal prodding or from the FDA. This is going to be something that’s going to be looked at very closely in the trial. Certainly it has come down the pike to us investigators that that’s going to be evaluated carefully.

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Bempedoic acid monotherapy and its combination with ezetimibe for lipid lowering in patients intolerant to statins. 

Bempedoic Acid for Lipid Lowering 

We’re going to talk about diet because it’s important, and I know the listeners like to hear the opinion of veteran clinicians like yourself. You’ve spoken of the Mediterranean diet. Manesh, Norman, Linda, what’s your favorite diet for our patients who are at high risk related to hypercholesterolemia and vascular disease?

I have a very simple thing that I tell my patients because I don’t have time to describe. I could send them to websites for the Mediterranean diet and so forth, but I tell all my patients to look at the nutrition information. I tell them it’s not the total fat that’s bad; it’s the saturated fat.

Which is even worse than the cholesterol in the food, correct?

Exactly, yes. The formula was derived in the 1960s, I think, in metabolic ward studies: saturated fat has 2 times the effect vs cholesterol. I tell them, “Look at that saturated fat. Keep it 2 g or less in the portion you’re going to eat.”

You know, I’m a big fan of the Mediterranean diet. I know it’s not a very sexy answer. There are people who like to do intermittent fasting and all these other varieties that get headlines. But I’m a big fan of the Mediterranean diet, which seems to win all the time.

On my dietary front, I’ll say the following: It depends on goal. Over the last few years I’ve lost some weight. If your goal is weight loss vs heart healthy—they’re often linked, but weight loss has some different things you can do vs heart healthy. I absolutely agree that the Mediterranean diet—the right kinds of fats, low carbohydrates, vegetables, fishes, good meats—is good. And what I tell my patients, when they ask me what I did, is that eating between only certain hours. 

A couple of things that are really important for people to understand is that your brain can use glucose. If you give your brain glucose for energy—straight glucose, fructose, some of those things—it does start to say, “ I don’t need to save all that other energy.” From a metabolic perspective, stay active. Some of these apps and other things, what they talk about is “keystone” habits. Can you do some activity in the morning and think about your health? Can you then at least in some way think about your plate?

I show them the 12 o’clock plate and say if you’re eating between 10 and 6 o’clock, that’s where vegetables are; here’s where protein is; this is where carbohydrates are. A small portion of the plate is carbohydrates, plus good types of proteins, mostly vegetables. It can’t be too complicated. Has to be pretty simple that they can look at their plate every day. That will make a difference. Otherwise we get into really complicated scenarios.

What most people are trying to do is say, “Is that a good nut? Should I not be eating that? Is that a bad fruit? Is that a good fruit?” That gets really complicated, even though I know low glycemic index exists. I appreciate that we think about what the types of saturated fats and nonsaturated fats are.

That enthusiasm of all those various meticulous complicated ways to approach eating patterns after awhile wanes, and the person is back to the drive-through.

That’s right, and the drive-through is easy, that’s for sure.

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Role of dietary and lifestyle modifications as part of lipid management. 

Dean Karalis, MD

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