Hearts & Minds Blog

The History of LDL-Cholesterol with Dr. Antonio Gotto | Beyond Statins: The Evolution of Cholesterol Lowering Treatments

Tim Mayleben

President and Chief Executive Officer

Antonio M. Gotto, Jr., MD, DPhil

Dean Emeritus, Weill Cornell Medicine, and Provost for Medical Affairs Emeritus, Cornell University

In Part I of our “History of LDL-cholesterol” blog series, I sat down with cardiovascular and lipids specialist, Dr. Antonio M. Gotto, Jr,. to explore the discovery of cholesterol and the development of statins. To continue our conversation focused on cholesterol-lowering treatment options, our next session was centered around therapies that have emerged after statins, and how they have changed the cholesterol treatment landscape. Dr. Gotto’s expertise and years of clinical practice always make for an informative and insightful discussion. Read on for highlights from Part II; our “beyond statins” conversation.

Tim Mayleben (Tim): It’s great to continue this conversation with you, Dr. Gotto. As you know, in our initial discussion, we reviewed the history of statins and approved statin treatments. Now, let’s dive into the various cholesterol-lowering treatments that have come to fruition following the discovery of statins. Kicking things off, what therapies do you see in development today that have caught your attention.

Dr. Antonio Gotto (Dr. Gotto): Well, if we just start with post-statins, there have been two types of drugs approved for which there’s evidence-based research indicating they give additional reduction in events on top of statins. The first of those was ezetimibe and the IMPROVE-IT study, where there was a statistically significant reduction in cardiovascular events in the five-year endpoint when ezetimibe was used in acute coronary syndrome patients on top of statins. And then more recently, we have the PCSK9 inhibitors. There were two trials presented at the last American College of Cardiology meeting in March, in which there was a demonstrated reduction of events by about 15-20% on top of maximally-tolerated statin therapy.

These are two drugs for which there’s evidence for LDL-cholesterol reduction with an approved indication for cholesterol lowering, but not for cardiovascular risk reduction at this time.  Merck applied for a cardiovascular disease risk reduction indication for ezetimibe based on the IMPROVE-IT trial, but the FDA denied it. And there hasn’t been sufficient time at this point for the results of the FOURIER trial with evolocumab to be reviewed and an indication sought in cardiovascular risk reduction.

Tim:  So I’m sure you’ve seen the data on the PCSK9 prescription volume which has been low. Of course, ezetimibe has been very successful along with its cousin Vytorin, which is ezetimibe in a fixed dose combination with a statin. But do you see patients with hypercholesterolemia that still have unmet needs? In other words, could you explain the lack of uptake for the PCSK9s as evidence that there are unmet LDL-cholesterol lowering needs for patients with hypercholesterolemia?

Dr. Gotto: The market uptake for PCSK9 is related firstly, to the difficulty in getting the approval to get the drug paid for and, secondly, the cost of the drug. So, I think those are two major barriers. And so whether or not the payers will consider a 15% reduction in events over and above the top dose of statins as sufficient evidence to make it easier to get the drug, or less costly to get the drug, remains to be seen.

But there are still unmet patient needs, specifically those who are considered statin intolerant. There is a need for drugs to treat patients not at goal who can’t or won’t take statins and thus aren’t benefiting from them.  And the PCSK9 inhibitors, with their expense and being difficult to obtain, may or may not be the answer to it. There may be room for other drugs that are less expensive and don’t require an injection – which some patients object to.

Tim: How long do you think it will be before the PCSK9s have a measurable impact on the LDL-cholesterol lowering treatment landscape, and what impact do you think they will ultimately have? As you were saying earlier, the payers are certainly restricting access and the price alone is also a hurdle for both physicians and patients. Even if successful in getting their prescription approved, the patient co-pay can be hundreds of dollars a month. That can be self-limiting in terms of the number of prescriptions filled. Do you think it’s going to take longer for the PCSK9s to have an effect on the overall treatment landscape?

Dr. Gotto: I think you have to judge the future in part based on the past. And if you’ve got a curve that’s slowly increasing, with a relatively modest slope, we’re not going to see a big jump or decrease without a sea change event.  I think there will be some increased uptake if a CV risk reduction indication from the FDA is obtained.  This would translate into a broader utilization than what is being done now; for example, in some states and with some payers, the reimbursement for PCSK9 inhibitors is restricted only to patients with familial hypercholesterolemia.  Also, in the long-term, if patients pressure payer policy, PCSK9s could become less restrictive; if they are easier to obtain and cost less, and if doctors become more accustomed to their use.  All of these factors could contribute to increased utilization of PCSK9 inhibitors.  I think there will be some increased uptake when and if they get a cardiovascular risk reduction indication. But I think it’s going to be a more gradual increase than a jump.

Tim: Until the FOURIER data came out, there was a lot of speculation about whether 70 mg/dL was the right LDL-cholesterol target, or whether there was a so-called J-curve such that, if you continued to go lower, you were going to start to see less of a benefit – for example as you do in A1C, in blood pressure and in weight loss. Do you believe that there’s a J-curve associated with LDL-cholesterol lowering? Or do you believe even lower is better? And I think more recently we’ve heard too that lower for longer is better. That is, the longer you can keep your LDL-cholesterol lower, the better. Do you have a target in mind? Do you think LDL-cholesterol lowering targets are going lower?

Dr. Gotto: Well, the answer is we don’t know. When a group of doctors were asked whether they had any reservation about getting LDL-cholesterol down as low as possible, some do and some don’t.  Personally, I feel a bit uncomfortable when you reach extremely low levels.  At birth, in cord blood, where you can diagnose familial hypercholesterolemia, the usual range of LDL-cholesterol is about 40 mg/dL.

So, we have to say we don’t know. We haven’t yet seen LDL-cholesterol that was induced by drugs where we could clearly identify some clinical abnormality or adverse event. We know that in abetalipoproteinemia where there is no apolipoprotein B formed, that there are severe defects – cardiovascular, nervous system, eye, retina, spine. But it’s been speculated much of that’s due to the absence of fat soluble vitamins. But still, I think we need some apo B. How much an individual would need, we don’t know yet.

Tim: Going off this, I wanted to ask you about statin side effects. There are a number of observational studies that have suggested that statin intolerance is not truly intolerance to statins, but is instead in the person’s head or could be a reaction to something else the patient is taking but gets blamed on the statin. Do you have a view on statin intolerance and how to deal with patients who say that they won’t or can’t take a statin?

Dr. Gotto: I think it’s a very heterogeneous group of individuals. I do believe there are some patients that have symptoms on statins. Until we have a way of measuring symptoms, it’s difficult to say. But there are patients who, for example, historically run 15 or 20 miles and on statins they can’t run over five miles. There are some who have been on statins and develop statin intolerance who can tolerate only a low dose of the statin. But I do believe there are some patients who just are not able to take statins, whether it’s related to psychosomatic factors or to some side effect that they experience with the GI tract or muscles.

Tim: And so does that alone suggest having an alternative oral option would be beneficial to offer patients with hypercholesterolemia who are at high risk?

Dr. Gotto: It’s always good to have treatment options for patients because you can do statistical analysis and try algorithms or use computers to make diagnoses, but every patient is an individual. There are so many different variables that you can’t just prescribe a one-treatment-fits-all. So, having multiple options certainly is an advantage both for physicians and patients.

Tim: You have a historical perspective as a treating physician using non-statin therapies that is extremely valuable. Tell us about some of the specific patient situations that you found these alternative therapies most useful.

Dr. Gotto: That’s true; for half my career, I didn’t have statins available to me as a treatment option, and I’ve been working for 40 years. So yes, I used everything in the book, approved and non-approved therapies, until we had statins. They’ve changed the landscape more than anything else in preventive cardiology. I’ve also used ezetimibe since the approval of statins, and continue to use some of the other drugs in selective patients. In a few cases I’ve used PCSK9 inhibitors in patients who have severe familial hypercholesterolemia.

Tim: Shifting our focus to bempedoic acid – do you like its mechanism of action? Do you like the target, ACL? Do you worry at all about the fact that bempedoic acid and statins work to lower LDL-cholesterol on the same pathway? Now that we know it’s a prodrug and it’s not active in anything but the liver cells, does that potentially answer the question about why we don’t see a lowering of plasma triglycerides? Maybe we’re seeing the lowering of triglycerides only in the liver?

Dr. Gotto: Well, I think it’s a very interesting mechanism. The therapies thus far that have been shown to be effective in reducing cardiovascular events all work through the LDL receptor – whether it’s bile acid sequestrants, which cause malabsorption of bile acids, reduces the bile acid level in the liver and diverts more cholesterol in the bile acid; whether it’s ileal bypass surgery, which does the same thing surgically that the bile acid sequestrants do orally; or whether it’s the statins, which are competitive inhibitors of HMG-CoA reductase or ezetimibe, which decreases the absorption of cholesterol in the GI tract. All of these upregulate the LDL receptor by pulling more cholesterol out of the body or by blocking the synthesis of cholesterol. Bempedoic acid, by inhibiting the formation of acetate, works on the same pathway.

But bempedoic acid may have a number of advantages compared to the other mechanisms, particularly the statins, since bempedoic acid is specific to the liver. It therefore may be free of the muscular side effects which are the most serious adverse events associated with statin therapy, particularly in high-dose statin therapy. And since it’s not activated in the pancreas, it’s possible that one might also be able to avoid increase in diabetes, which would be a big plus.

Tim:  Thanks for sharing your perspective, Dr. Gotto! I want to thank you for helping us explore the therapies developed since the discovery of statins.

I look forward to speaking with you again soon for the final part of our blog series on LDL-cholesterol, where we’ll ask you to look into your crystal ball and talk with us about the future of LDL-cholesterol lowering.

The full interview has been edited for clarity and length.

Dr. Gotto is a member of the Esperion Board of Directors.  He also has the following conflicts of interest to disclose: consultant to Amgen, Merck, and Kowa.