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Lowering LDL with the New PCSK9 Inhibitors

Eckel2Exclusive interview from AACE Orlando, May 2016

This is Part 3 of a 3-part interview. Part 1 |Part 2

Robert H. Eckel, M.D., University of Colorado; Charles A. Boettcher Endowed Chair in Atherosclerosis; Professor of Medicine; Division of Endocrinology, Metabolism and Diabetes, and Cardiology; Professor of Physiology and Biophysics; Program Director, Adult General Clinical Research Center

With Steve Freed, Publisher, Diabetes in Control

Steve:  I’d like to get back to cholesterol.

Dr. Eckel: That’s what I was here to talk about.

Steve:  That’s where your expertise is. Now we have these new drugs, I guess primarily for when people can’t take statins, or statins may not be as effective. For people who have the familial type of cholesterol, where it’s in their genes. Their body just overproduces it. What was your talk about? How low should an LDL be? Are we sure the LDL is the most important part? There are other aspects of cholesterol, total cholesterol, HDL, et cetera. It’s been changing over time, what we should be focused on. So from this point forward, what should we be focused on and how low should it be? Obviously those people with diabetes are at greater risk, so therefore we have to look at that a little more closely. So for people with diabetes, where should that number be?

Dr. Eckel: Let’s talk about diabetes as a whole and then focus on type 2, because that’s where the randomized control trials have taken place. So I’m privileged to be part of the cholesterol guideline for the HA and the ACC also and diabetes was one of the four categories for which that therapy is indicated, no matter what the LDL cholesterol level is. Now we’re talking about people between the ages of 40 and 75 and that’s where the clinical trials have been done. Having diabetes is a statin indication. In the presence of a previous heart attack or stroke, that LDL lowering therapy should be intensified to high dose statin if tolerated. But for primary prevention in the patient with diabetes a moderate dose statin is indicated. So statin should be given to all patients with diabetes 40 to 75. Well, you can say I have a patient with no risk who’s 40 and she doesn’t like taking statins. The idea is you have to make an individualized decision. But in general the evidence suggest that patients with diabetes should be on a statin. Now the lipid disturbances in diabetes are not an LDL elevation typically, it’s more triglyceride elevations and lower levels of HDL cholesterol. Our guidelines couldn’t find sufficient evidence to say what we should do about triglycerides or HDL. But the story on HDL is now pretty clear: we shouldn’t use drugs to treat HDL cholesterol under any circumstance. Now high triglycerides, I think there is a theme that suggests that if your triglycerides are elevated and you’re on a statin adequately that maybe a fibrate should be used to lower those triglycerides. That’s a theme that relates to post hoc analyses of existing studies. We can’t promote that as evidence based therapy. This is something that I think the clinician, even primary care or CDs need to understand a little bit that triglyceride lowering may be beneficial and the fibrate at this point would still be the drug of choice. As a pharmacist you know that fibrates and statins interact so you’ve got to be careful with dosage and co-prescriptions, but nevertheless, I personally have a lot of people on fibrates and statins together for the benefit of risk reduction with LDL and then with TGs. Back to levels, our guidelines said that levels weren’t evidenced based. But that doesn’t mean that you can’t set levels, which I do routinely. Basically for secondary prevention of diabetes, an LDL under 70 should be our goal. If you look at the Improve It trial which looked at the addition of Ezetimibe on top of the statin, under 55 might be better than under 70, because of the diabetes patients that really drove the outcome of that study. If you exclude patients with diabetes in Improve It, there’s no benefit with Ezetimibe. But when diabetic patients are included and they are examined as a subgroup, their benefit was pretty convincing. Under 55 for that high risk patient with diabetes with previous heart attacks, Ezetimibe is perfectly reasonable. Ezetimibe as an add-on to statin may be useful in achieving that outcome. Now for primary prevention in diabetes, let’s take a 55 year old woman who has type 2 diabetes and who has not had a heart attack and her LDL is say 110, there a modern intensity statin would lower her under a 100 and I think that’s reasonably acceptable for treatment of primary prevention patients with type 2 diabetes.

Steve: So for those persons who are at risk for coronary artery disease, what was the number?

Dr. Eckel:  Well, with diabetes, under 100 for primary prevention, that means there is no history of an event, those people with a previous event at least under 70 and perhaps under 55 based on Improve It now. Now the drugs I talked about today are PCSK9 inhibitors. These have dramatic LDL lowering effects. The FDA has approved this for people with familial hypercholesterolemia, that would be basically an LDL above 190 untreated and patients with moderate to high risk that don’t have adequate LDL lowering on maximum tolerated statin therapy and then finally patients who are statin intolerant. When you work at a lipid clinic at a referral institution like I do, I get a lot of statin intolerant patients. So there, their LDL cholesterol is going to be inadequately lowered because they’re not on an adequate dose of statin or can’t take it at all. They’re the PCSK9s if we feel the LDL is too elevated, then that would be another option for treatment.

Steve: These new drugs are very expensive. What have you seen as far as, most people probably can’t afford it, when you look at the costs I think $1500 a month.

Dr. Eckel: It’s a little bit less, but not much.

Steve: Well even at say $1000, that’s still…

Dr. Eckel:] It’s 14.4 or 14.5 a year.

Steve: What do you do if a patient comes in and they need the drug, is it being covered from what you see right now?

Dr. Eckel: Well if you asked me this question in September or October of last year I would have said we’re having trouble getting it covered. Now I have over 80% of my prescriptions filled because I followed the indications that are FDA approved and document the history of an event or document that they had FH on entrance. Now keep in mind, diabetic patients can get FH too, it’s just not the typical lipid abnormality we see in diabetes, but yet patients with diabetes often have heart attacks and strokes, and their LDL cholesterols may be 90 on maximum statin therapy. I think those people need a lower LDL. Now, how low it should go, whether we have a benefit that plateaus at 55 or 40 or 25, we don’t know yet. Secondly, long-term, I’m talking about 10 and 20 years of very low cholesterols like under 25, is that going to be harmful? We just don’t know that either. I don’t think this is an adverse effect that is going to show up within 18 months or two years of very low LDL cholesterols. I’m not predicting it will come up, all I’m saying is we just don’t know. The long term safety would have to be validated before we would make a confident statement there.

Steve: And one of the things I know you are talking on is: how low is too low?

Dr. Eckel: I kind of set under 40 as maybe a bit of an alert to the practicing physician that that may be a level at which we’d be comfortable achieving but not much further. I call under 25 very low. I will alter therapy if it’s under 25 and relax therapy. Keep in mind that’s relaxing PCSK9s, not statins, because the statins are evidenced based. There we have a choice of two different drugs. Evolocumab is only one dosage, the 140 every two weeks whereas Alirocumab can be dosed at 75 every two weeks or 150. So Alirocumab gives us an advantage, I’m not promoting the drug, it’s simply a dose based drug that gives you an option for using a lower dose. I use both drugs and by the way which drug the patient gets is based on what company approves those drugs, right? I don’t have a favorite drug, I just want to have it approved for those patients I think need it.

 

This is Part 3 of a 3-part interview. Part 1 |Part 2