Hearts & Minds Blog

The History of LDL-Cholesterol with Dr. Antonio Gotto | Beyond Statins: The Future 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 and Part II of this series we explored the evolution of LDL-cholesterol: from the early days of its discovery to the statin era boom. Now, we sit down again with cardiovascular and lipids specialist, Dr. Antonio M. Gotto, Jr, for the third and final installment of “The History of LDL-Cholesterol” to get his perspective on the future of LDL-cholesterol lowering. Read on for highlights from our conversation on the evolution of cholesterol-lowering treatments; the implications of bempedoic acid-based therapies for physicians, patients and payers; and Dr. Gotto’s predictions for the future of cholesterol lowering treatments.

Tim Mayleben (Tim): During our last discussion you shared your enthusiasm for the potential of both bempedoic acid as well as the bempedoic acid / ezetimibe combination pill. Now that we’re on the cusp of reporting top-line results from the global, pivotal, Phase 3 program – starting in March and spanning the next several months – from your perspective, what are you most interested in learning from these studies?

Dr. Antonio Gotto (Dr. Gotto): First is the efficacy of bempedoic acid and the bempedoic acid / ezetimibe combination pill in reducing LDL-cholesterol. In the Phase 2 program, we saw close to a 50% reduction of LDL-cholesterol with this combination pill compared to placebo, and upwards of 60% when these two are added on to a statin, which, as you know, is comparable to the reduction rates associated with PCSK9 inhibitors. In Phase 3, I would expect to see significant incremental lowering of LDL-C on top of maximally tolerated statins.

Secondly, the safety results. There have been more than 1,000 patients in Phase 2 studies over the course of several 12-week studies. This is longer than statin-based studies, which typically lasted four to six weeks. During Phase 2, there have been positive safety signals, which I find very encouraging.

Tim: Speaking of safety, do you see any safety and tolerability advantages of bempedoic acid?

Dr. Gotto: The liver specificity of bempedoic acid is one of its major advantages. Patients complain of muscle symptoms or decreased exercise tolerance while taking statins. Because bempedoic acid is a pro-drug that is only active in the liver, the muscle toxicity that is associated with statin use is not expected to occur with bempedoic acid.

Tim: On the topic of statins, we see bempedoic acid as truly complementary to other lipid-lowering therapies, including statins, ezetimibe and even PCSK9 inhibitors. How do you see these once-daily, oral pills fitting into the current treatment paradigm?

Dr. Gotto: I predict physicians will welcome both the bempedoic acid and the bempedoic acid / ezetimibe combination pill for their patients who are not at goal and require additional LDL-cholesterol lowering, and for their patients who are not able to tolerate statins, or can only take such a small dose of statins that they too need additional LDL-cholesterol lowering. These pills appear to be safe, we know they are effective, and they are certainly less expensive than biologic options without the requirement for injections.

Of these factors, the biggest benefit to physicians in my view is that they will be able to treat those patients who either cannot tolerate statins or who do not get sufficient LDL-cholesterol reduction with statins. As more and more studies accumulate, data reinforce that “lower is better” when it comes to LDL-C lowering and the impact on reducing cardiovascular risk.

Tim: Shifting gears a bit, one of the things you’ve heard us talk about is how, historically, the most significant hurdle that drug developers had to worry about was making sure the drug got approved and on to the market.  Now, as we look at the increasing role of payers in controlling access to therapy, how do you see bempedoic acid and the bempedoic acid / ezetimibe combination pill impacting the payer environment for LDL-cholesterol lowering therapies?

Gotto: I think bempedoic acid and the combination pill will be welcomed by the payers. Over the last few years, payers have had to consider very expensive alternatives with orphan indications. Also, the lack of convenience and insurance coverage of the injectable PCSK9 inhibitors has been a major disincentive to the acceptance and use of the drug. With this in mind, an oral monotherapy or combination pill that’s effective, safe and easy to adhere to will experience a much different reception.

Tim: It’s interesting because it takes into account that it’s about the price of the drug, but also the convenience of delivery. One of the things that we keep reminding people is that when a patient goes on to a PCSK9 inhibitor, it’s NOT a switch from an oral therapy regimen entirely to an injectable regimen. They’re taking their injection but they’re still having to take the statin every day.

Dr. Gotto: Right. And we know most people would want to stay with an all-oral regimen.

Tim: Going back to something you referenced earlier. Cardiovascular outcomes studies continue to validate what we’ve known for a long time: LDL-cholesterol lowering is a truly valid surrogate endpoint for cardiovascular outcomes and cardiovascular disease risk reduction. With our own CLEAR Outcomes study ongoing, what implications do you think these studies will ultimately have on the treatment landscape?

Dr. Gotto: Outcomes studies consistently prove that we’re looking at getting lower and lower levels of LDL-cholesterol. After IMPROVE-IT, I wrote in the Journal of Clinical Lipidology, “The LDL Hypothesis: Proven Again with IMPROVE-IT.” When initially treating hypercholesterolemia to reduce cardiovascular events, we started with the most high-risk patients, and then we found that lower risk patients also benefit from lower levels of LDL-cholesterol. Most importantly, so far they’ve been achieved with relative safety.

Tim: One other question that comes to mind is the point of difference in the length of follow-up of these different trials. We know that there was a 26-month mean follow-up in the FOURIER trial; it’s expected that ODYSSEY will be complete closer to three years; CLEAR will be complete after four years. What role do you think different lengths of dosing may play in the risk-reduction that we observe in these studies?

Dr. Gotto: The duration of the studies impacts the decrease in cardiovascular risk, which typically begins to be observed within one to two years. The longer these studies are carried out, the more events the therapies will reduce and therefore the stronger the statistical power of the study will be.

Tim: Looking ahead at our CLEAR Outcomes trial, if we were to be reviewing the data with you in a few years’ time, what are your predictions for what we might see?

Dr. Gotto: I’d expect to see a reduction of events proportionate with the LDL-cholesterol reduction. If the mean LDL-cholesterol level was 135 and you got about a 30% reduction with bempedoic acid, then you would expect a reduction in events of approximately 15-20%.

Tim: There are whisperings that the anticipated new guidelines from the ACC and AHA may reintroduce target goals. What are your predictions for the new guidelines?

Dr. Gotto: They may be reluctant to reintroduce the term “target” given there was such an uproar over the previous guidelines. However, it’s hard for me to imagine them not having effective measurements in place which would indicate the level of LDL-C at which you would administer a drug and a goal of treatment. It’s all speculation right now, so we’ll just need to wait and see.

Tim: We certainly will. How might these new guidelines translate to patient care?

Dr. Gotto: Though there are about 40 million patients in the U.S. currently on LDL-cholesterol lowering treatment of some kind, I think there will be a modest increase in the number of patients treated – but there will be more emphasis on more intense treatment methods. I think there will be some trade-off between the absolute benefit and the risk of taking the drug.

I also think these guidelines may suggest we should start treatment at an earlier age, without drugs. For example, we should be recommending lifestyle modifications at a younger age, such as implementing diet and exercise, to try to prevent the build-up of plaque which starts without any known risk factors.

Tim: We’ve definitely made great strides in the management of cardiovascular disease by addressing patients in younger age demographics and the need to adjust lifestyle choices for cardiovascular health. Beyond lifestyle, we’re at a point where we have a series of LDL-cholesterol lowering therapies, including statins, ezetimibe, fibrates, nicotinic acid, PCSK9 inhibitors and, soon, bempedoic acid and the combination pill. Do you think the focus for treatments is going to shift now to other lipids that potentially impact cardiovascular risk?

Dr. Gotto: I think LDL-C is the major focus, and will remain the major player for a long time to come. These other targets may identify subgroups that would benefit from other therapies, but I don’t think they would replace the LDL-cholesterol reduction.

Tim: Dr. Gotto, thank you so much for your time and sharing your expertise for this series. Over the course of our discussions, you’ve provided a robust history and explanation of lipids and atherosclerosis, the evolution of the treatment landscape and, today, a look in to the future. Before we part ways, is there anything else you would like to add?

Dr. Gotto: It’s impressive that in 1928, the person who won the Nobel Prize for the discovery of cholesterol didn’t have the right structure. Four years later, they had the structure worked out correctly, but it took another 30 years and the efforts of many scientists and laboratories before the pathway for cholesterol biosynthesis was established. And then another 25 years for the introduction of an inhibitor of HMG-CoA reductase, the rate-limiting step of cholesterol biosynthesis. Before the sea change occurred with the statins, drug development was peppered with failure.

Now, with bempedoic acid, we are poised for another important moment in this history. We’ve come a long way.

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.