Yehuda Handelsman, MD: Paul mentioned bempedoic acid, which is part of a new class, like ACL [adenosine triphosphate-citrate lyase] inhibitors. Christie, could you describe how this class works?

Christie Ballantyne, MD: We are familiar with statins which inhibit HMG-CoA reductase, which is the right limiting step for cholesterol synthesis, and ATP [adenosine triphosphate] citrate lyase is above that in the pathway. One of the interesting aspects of the bempedoic acid is that it is a pro-drug, it gets converted in the liver to the active form. This theoretically may reduce the muscle side effect, which is our biggest complaint that we get from statins, rhabdomyolysis is rare, true myopathy, but many people complain of myalgia and other musculoskeletal side effects. The study has been looked at. The drugs, as Erin mentioned, are available in a monotherapy pill, as well as a combination therapy pill. I see a lot of statins in tolerant patients, so this combination therapy pill is one that gave around 40% study in diabetics and nondiabetics, and 38% compared to placebo. As a monotherapy, it has been studied on top of high intensity statins and was around 18%. Some of us have used very low doses, 5 mg 3 times a week of rosuvastatin, which was given around 25%. Each patient has a different response, and we presented this data recently. The manuscript is in the pipeline but if people were not on statin or the lower dosage, over a half of the patients got greater than 30% reduction. This is a viable option.

The reason I bring that up is the OUTCOMES trial is being done in patients who are statin intolerant. In other words, they are not able to tolerate either the starting dose or there are no statins, and that’s an important population. If you look percentage wise, there are more women than men in terms of statin intolerance. As a clinician we are always treating one patient at a time, so you must plan. Paul, you mentioned going to 80 Bitorva [ezetimibe and atorvastatin], but if they don’t want to take 80, they are not going to take it. They would say I feel bad, and for you to say, “that’s just in your head,” I mean, what feelings are not in your head. You want to make sure you don’t see that patient again, just tell them that we know this is not a real effect with it. I am very curious now that trial has been fully enrolled, it is ongoing. Hopefully we will see the data and an announcement sometime.

Handelsman: It’s called CLEAR-outcomes.

Ballantyne: CLEAR-outcomes. It's a large study.

Erin D. Michos, MD, MHS: And enrolled nearly half women.

Ballantyne: It's one of the only ones, the only one.

Michos: Women tend to be very under-enrolled in cardiovascular clinical trials, relative to the disease burden in the population, but in this trial, there's about half enrollment of women, which is important. Likely because of the eligibility of statin intolerance, as this affects women more. It's an interesting signal that bempedoic acid seems to lower CRP [c-reactive protein]. The outcome of this trial will be interesting to see whether the benefit would be anticipated by its LDL [low-density lipoproteins] reduction alone, or whether it's a greater reduction because of the CRP. The other interesting thing is, at least in the trials that have been published so far, we don't see the increased risk for new-onset diabetes like we do in the statins trial. We'll have to see the CLEAR-outcomes trial, but it’s encouraging that it doesn't seem to make glycemia worse.

Ballantyne: The group that ends up having the statin intolerance because they have the baseline data, is women, and a lot of diabetes, high BMI, and high CRP will be in that group, too; women have higher CRPs than men in general.

Handelsman: If you take this combination pill that you mentioned, bempedoic acid and azetimibe, those improved in terms of adherence and treatment, but the 40% more or less reduction in people with diabetes, and you take the study that diabetes study, where the PCSK9 inhibitor, and the reduction there was between 40-44% in people with diabetes; it can be almost comparable in terms of their impact.

Paul S. Jellinger, MD, MACE: Statin intolerance was bought up, and it's a good time to remind everyone about a recent study, a meta-analysis of 300,000 patients looking at statin intolerance, the so-called nocebo effect, which got a lot of publicity. When they dissected the true incidence of what they believed, those that conducted the study, the true statin intolerance was about 6-9% of the population; the rest could be sorted out as unrelated. However, you cannot convince a patient who tells you they have myalgias on a statin, that there's a 94% chance that it's not the statin.

Ballantyne: You can reduce the dose, change the statins, or give a statin holiday, and we do all these things, but as you said, you want to keep them at least on some dose statin, even a very small with combination, because we have so much data. Even a low dose of statin, 5 milligrams of rosuvastatin three times a week, 2.5 milligrams daily, gives you a nice LDL reduction. We try to do that, but it is a partnership with the patient. It's like we're guides, we can tell them which way to go, but they're driving the car; it's their car, their heart attack, their cardiovascular health, so they're the ones who are ultimately going to be the drivers of their health. We must work with them; having the concept, “you must take this, it doesn't matter what your symptoms are,” won’t work. It's a different world.

Matthew J. Budoff, MD: There's 2 tricks that I've used. One is, you get a coronary calcium scan, or something like that, and show them that they have plaque, and suddenly this statin intolerance may go away because they perceive the need to take it. We also have Doctor Google whispering in their ear that statins are terrible, and if you Google the wrong thing, you get the wrong answer and they have all these, “your diabetes, muscles, liver, cognition, it's so dangerous.” Starting slow, you may have talked about 3 times a week, but sometimes I start them at once a week, and then I check in, “You're doing OK? You don't feel bad with that? Let's try to get up to speed.” If you go slowly and titrate them up, sometimes you can overcome that, but they perceive it.

Ballantyne: It's working with them.

Budoff: Yeah, they perceive a problem? They're not going to take it and we have alternatives now.

Handelsman: I like that you mentioned imaging, because at the end of the day, the number of cholesterols, the LDL number, is just a number; it's nothing they feel or see, but if you show them imaging, it changes perception. Heart attack is the end, but plaque on the vessel is the beginning of the end; that's an end-organ damage already going on.

Budoff: Both the European guidelines and the DCRM [Diabetes Cardiorenal & Metabolism Institute] guidelines talk about—and we'll have more guidelines coming out from other organizations—coronary calcium score being elevated.

Handelsman: Correct.

Budoff: Even the AHA/ECC [American Heart Association/ Emergency Cardiovascular Care] guidelines recognize this now, that an elevated coronary calcium score is a high-risk state, and a score above 300 is probably the equivalent of secondary prevention where we could pull out some of these bigger guns like Paul talked about.

Ballantyne: There's a new AC [adenylyl cyclase] pathway I've been involved with, and it'll have a nice section you'll like on coronary calcium scoring, Matt.

Handelsman: That's cool, that's nice, about time.

Transcript Edited for Clarity