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Challenges and opportunities for addressing hyperlipidemia in the primary prevention population

Supplements And Featured PublicationsProgress in Addressing Hyperlipidemia in the Primary Prevention Setting

A Q&A with Steven E. Nissen, M.D., M.A.C.C.


Chief Academic Officer, Heart, Vascular, & Thoracic Institute

Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic

Professor of Medicine, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University in Cleveland


Chief Academic Officer, Heart, Vascular, & Thoracic Institute

Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic

Professor of Medicine, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University in Cleveland

MHE: For many decades, statins have been the cornerstone of therapy for hypercholesterolemia. Could you describe some of the unmet needs with statin therapy?

Nissen: Statins are fantastic drugs. They have saved many lives over the last three decades and they are generally very well tolerated. However, there are several unmet needs. There are still people who have very high low-density lipoprotein cholesterol [LDL-C], including those with heterozygous familial hyperlipidemia, in whom we are not able to reduce LDL-C to levels that we think would be optimal, even on the highest doses of the most effective statins. So, statins do have limitations and we need other therapies to get patients to goal. A second unmet need — and this remains a controversial area — is that some patients simply do not tolerate statins. These patients may not tolerate statin doses high enough to reach LDL goals, or they may not tolerate statins at any dose. Alternatives are needed to be able to treat those patients who are eligible for statins according to the guidelines but who do not tolerate statins.

MHE: Within the past decade or so, several nonstatin therapies for hypercholesterolemia have been developed and approved by the FDA, including ezetimibe, PCSK9 inhibitors (monoclonal antibodies and inclisiran) and bempedoic acid. How have these nonstatin therapies helped to address unmet needs among patients with hypercholesterolemia?

Nissen: Let’s start with the oldest of them, which is ezetimibe. Ezetimibe is now available as a generic and it is very commonly used. Ezetimibe is effective at moderately lowering LDL-C — this drug provides about an 18% reduction on a background of statins, and it is generally very well tolerated.

The proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors are very powerful drugs. They remain relatively expensive, but they are very effective and can lower LDL-C as much as 50% on a background of statins. The monoclonal antibodies, evolocumab and alirocumab, are taken generally every two weeks by self-injection, and they are well tolerated. Many patients are willing to accept an injectable therapy. More recently, inclisiran, a short-interfering RNA that targets PCSK9, has been introduced. And after two starter doses, it’s an every-six-month therapy, but it must be given in a physician’s office. It is very effective and convenient for many patients, but some may not want to come to an office to get an injection twice a year. It’s not available as a home therapy.

Bempedoic acid, which is an ATP-citrate lyase inhibitor, has been on the market for a few years. An outcomes trial that is known as CLEAR Outcomes [NCT02993406] was recently completed, which showed that bempedoic acid reduced major adverse cardiovascular events [MACE] in both primary and secondary prevention patients with high LDL and high risk.1 Bempedoic acid, which is taken daily, has the advantage of being a prodrug, meaning that it is not active when taken orally. It has to be converted to an active form in the liver. This is advantageous because it means that bempedoic acid does not accumulate in muscle as an active drug. Patients who do not tolerate statins mostly do not tolerate them due to muscle-related [side] effects, and bempedoic acid has a low incidence of muscle-related [side] effects, and so bempedoic acid can be a useful option for statin-intolerant patients. It’s most effective as a combination of ezetimibe and bempedoic acid. Both drugs work independently, so that combination can lower LDL-C as much as 35% to 40% — a reduction that’s comparable to a moderate-intensity statin such as the 40-mg dose of simvastatin. This gives us an alternative oral agent that we can use in people who do not tolerate statins, and that provides meaningful reductions in LDL-C and cardiovascular risk.

MHE: What are some of the recent developments in terms of trial data supporting nonstatin therapies for primary prevention of atherosclerotic cardiovascular disease, or ASCVD?

Nissen: The CLEAR Outcomes trial was a very successful, large scale, 14,000-patient trial conducted over several years. We typically have to study these drugs for 3 to 5 years to observe their benefits.1 The results showed a significant reduction in MACE in patients who either did not tolerate statins at all or could only tolerate a dose that was below the lowest dose approved by regulatory authorities. In other words, if you could not take 10 mg of atorvastatin daily or if you could only take it twice a week, then you were eligible for the CLEAR Outcomes trial. This was the first time that an alternative to statins was studied in statin-intolerant patients. The result was a hazard ratio for the primary four-component MACE outcome of 0.87, a 13% overall reduction. And for the three-component MACE outcome of death, stroke and MI, there was a 15% reduction. It was a particularly effective drug for reduction of risk of myocardial infarction with a hazard ratio of less than 0.8, so more than a 20% reduction in myocardial infarction. These are very good results.

CLEAR Outcomes, unlike most contemporary studies, enrolled a population that included high-risk primary prevention patients, patients who had never had a cardiovascular event. About 30% of the total population was primary prevention patients, or about 4,000 patients. We did a secondary analysis of outcomes in the primary prevention patients,2 and in [those] patients, there was a very large reduction of about 30% for both morbidity and mortality. This is a very striking result. The results show that primary prevention patients who were often untreated and who have not yet had an event but have many risk factors and high LDL-C have the greatest benefit from lipid-lowering therapy.

MHE: Could you briefly describe the current place in therapy of each of the nonstatin agents in terms of primary prevention of ASCVD? Have clinical guidelines been updated to reflect recent evidence supporting nonstatin therapies for primary prevention?

Nissen: Clinical guidelines are very slow to change, and there will need to be some revisions based upon the most recent data. That being said, in guidelines from the American Heart Association and the American College of Cardiology, there is a very good recommendation for treating primary prevention patients who have a 10-year risk using the risk calculator of at least 7.5% and to consider treating them if their risk is greater than 5%.3 Again, statins are the mainstay of treatment. If statin therapy is well tolerated, these drugs are the first choice. We do not have yet primary prevention data on the PCSK9 inhibitors, but there is a very large trial currently underway using inclisiran to treat patients in the primary prevention setting.4 So, we will find out whether adding a PCSK9 inhibitor to patients in the primary prevention group will result in improvement in outcome. The bempedoic acid results I just mentioned are obviously very striking.1,2 No primary prevention data are available for ezetimibe, and such data probably will not be forthcoming now that it is a generic drug.

MHE: What is the impact of clinical inertia in relation to getting patients to goal LDL-C as part of primary prevention of ASCVD?

Nissen: Clinical inertia is an enormous problem. We frequently see patients who are high risk and have a very high LDL-C. They see a primary care physician and leave that office with the recommendation to make adjustments to their diet. Unfortunately, lifestyle changes generally can only lower LDL-C very modestly — 10%, occasionally 20%. If a patient’s LDL-C is 160 mg/dL, lifestyle changes alone are not going to get them to an optimal LDL level. Unfortunately, it’s been very difficult to get many patients in the primary prevention setting onto appropriate lipid-lowering therapy. Observational studies have shown that less than half of primary prevention patients who would be eligible for treatment according to the guidelines actually receive treatment.5 Seeing so many high-risk patients with suboptimal LDL-C who are not on therapy has been very frustrating for those of us who have spent a lot of time demonstrating that lower levels of LDL-C are beneficial. Unfortunately, we sometimes see them when they have their first event. It’s often a myocardial infarction and they may have irreversible injury to the myocardium. So, this is a very difficult problem. We need more education directed at the general public and we need more education for physicians to overcome clinical inertia.

MHE: Can you describe trials currently in progress that might impact clinical practice regarding primary prevention in the near future?

Nissen: VICTORION-1-PREVENT [NCT05739383], or V1P, is a trial being conducted by Novartis, the company that makes inclisiran.4 This large, long-term study is designed to determine whether high-risk primary prevention patients will benefit by the addition of inclisiran to their current therapy in terms of a reduction in morbidity and mortality.

MHE: Could you describe therapies currently in development for hypercholesterolemia? What additional options might be available to clinicians within the next five to 10 years?

Nissen: I will discuss a few treatments in development. One is inhibitors of angiopoietin-like protein 3 [ANGPTL3]. There is an ANGPTL3 inhibitor on the market that has been approved for homozygous familial hypercholesterolemia, and it is very effective.6 It is quite expensive, but it works in patients in whom nothing else works. So that’s certainly important. But there also are short-interfering RNA therapies for ANGPTL3 that are in development that may have some real benefits. There is, to my knowledge, at least one trial of a short-interfering RNA targeting apolipoprotein C3 [APOC3], which is another unique lipid target, and that is ongoing.7 One of the most exciting therapies, although it is a ways off, is gene editing, CRISPR-based therapies. The first data on CRISPR editing of genes for the PCSK9 gene were reported at the American Heart Association meeting in November 2023.8 When the gene for PCSK9 is edited, it is possible to permanently lower LDL-C by 50% or more. This is a single treatment that alters the gene. If these therapies prove to be safe and effective in additional studies, they will ultimately be approved.

MHE: Do you feel optimistic about the current state of cardiovascular care, particularly regarding primary prevention of ASCVD? Why or why not?

Nissen: I am not so optimistic. We have been struggling with raising awareness among both patients and physicians about the benefits of treating the primary prevention patient population. Despite all the educational efforts and all the public health awareness efforts, we are only treating perhaps half of the patients who could benefit. I think we need to intensify our efforts to educate both physicians and patients about the importance of interventions for high cholesterol in suitable patients. It could take decades to get to the place where we need to be. I also think that we need better ways to achieve adherence. I am optimistic about the long-acting drugs like inclisiran because I do think that they have the advantage that they can work for six months. And I am also encouraged by the CRISPR-based therapies because they can edit the gene and permanently lower LDL-C. That’s where I think the future may be in terms of getting more patients treated.


1. Nissen SE, Lincoff AM, Brennan D, et al; CLEAR Outcomes Investigators. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023;388(15):1353-1364. doi:10.1056/NEJMoa2215024
2. Nissen SE, Menon V, Nicholls SJ, et al. Bempedoic acid for primary prevention of cardiovascular events in statin-intolerant patients. JAMA. 2023;330(2):131-140. doi:10.1001/jama.2023.9696
3. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;140(11):e563-e595. doi:10.1161/CIR.0000000000000677
4. A study of inclisiran to prevent cardiovascular events in high-risk primary prevention patients. ClinicalTrials.gov. Updated January 29, 2024. Accessed March 8, 2024. https://clinicaltrials.gov/study/NCT05739383
5. Saeed A, Zhu J, Thoma F, et al. Cardiovascular disease risk-based statin utilization and associated outcomes in a primary prevention cohort: insights from a large health care network. Circ Cardiovasc Qual Outcomes. 2021;14(9):e007485. doi:10.1161/CIRCOUTCOMES.120.007485
6. Evkeeza. Prescribing information. Regeneron; 2023. Accessed March 8, 2024. https://www.regeneron.com/downloads/evkeeza_pi.pdf
7. Study of ARO-APOC3 in adults with familial chylomicronemia syndrome (FCS) (PALISADE). Updated June 12, 2023. Accessed March 8, 2024. https://clinicaltrials.gov/study/NCT05089084
8. Tremblay F, Kelly K, Shah S, et al. LBBS01 - A single administration of an epigenetic editor targeting human PCSK9 robustly and durably lowers cholesterol in vivo. Presented November 11, 2023, at the American Heart Association Scientific Sessions. https://www.abstractsonline.com/pp8/?_ga=2.17782015.7532578.1693882428-1949139275.1663003561#!/10871/presentation/17189

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