An important goal for people with atherosclerotic cardiovascular disease (ASCVD) is how to manage LDL-C (low-density lipoprotein-cholesterol).

Aggressive LDL-C management is essential to prevent cardiovascular events and death. However, many people still have higher-than-optimal LDL-C levels and are unaware of it. The LDL-C goal attainment rate among ASCVD patients in Korea, where cholesterol management is urgently needed, remains at 24.4 percent.

Furthermore, despite the important role that medication adherence plays in controlling LDL-C levels in ASCVD patients, the adherence rate among Korean patients is very low. A study analyzing claims data from the Health Insurance Review and Assessment Service (2012-2014) found that only 66.4 percent of patients with ASCVD continued to take statins and ezetimibe.

Against this backdrop, Leqvio (incliciran), a siRNA therapy shown to effectively reduce LDL-C with only two annual doses, won approval in Korea last June for patients with primary hypercholesterolemia or mixed dyslipidemia.

Leqvio is the first-in-class siRNA therapy approved in Korea. In a pivotal phase 3 clinical program (ORION-9, ORION-10, and ORION-11 studies), it demonstrated a reduction in LDL-C by up to 52 percent compared to placebo.

The twice-yearly physician-directed injections (initial, three-month, and then every six months) allow patients to manage their LDL-C with their healthcare provider without the fear of self-injection, and the low annual medication burden compared to daily high-dose statins or monoclonal antibodies administered 12 to 26 times per year, as well as the high level of treatment adherence and average annual LDL-C reductions, have led to high expectations in the clinic.

Korea Biomedical Review interviewed Professor Lee Oh-hyun of the Department of Cardiology at Yongin Severance Hospital about the importance of LDL-C management in ASCVD patients and the current treatment status in Korea, asking him about the clinical value and role of Leqvio.

Question: What is the LDL-C target level for ASCVD patients currently recommended by domestic and international guidelines?

Answer: Currently, the LDL-C target level for ASCVD patients recommended by domestic guidelines is as follows. According to the fifth edition of the 2022 Korean Guidelines for Dyslipidemia, the target LDL-C level for patients with peripheral vascular disease, carotid artery disease, and cerebral infarction is 70 mg/dL, and patients with coronary artery disease are recommended to maintain LDL-C below 55 mg/dL.

However, target LDL-C levels continue to be lowered. Specifically, the goal of maintaining LDL-C at or below 55 mg/dL was established because several clinical studies have shown evidence that LDL-C reduction provides additional clinical benefit. With the recent increase in the use of PCSK9 inhibitors and the upcoming expansion of the use of Leqvio, the target will likely be further adjusted. The European Society of Cardiology has recommended lowering LDL-C levels by defining a separate ultrahigh-risk group. However, LDL-C levels are better controlled in Asia than in the West, so 50 mg/dL remains the target.

Q: How many patients achieve this target LDL-C level in clinical practice?

A: Patients who do not reach their target LDL-C level, even with statins or ezetimibe, represent the unmet need for lipid-lowering therapy (LLT). In general, LDL-C reductions can be expected with certain medications based on a patient's cholesterol levels. However, there is a gap between expectations and treatment outcomes in practice.

For example, if a patient is prescribed a six-month supply of medication, most patients leave at least two weeks’ dose of medication even if they are reminded to take it consistently. Some patients even leave two to three months of medication untaken. This is due to low awareness of the disease and the need to manage LDL-C. Many patients also do not have a clear understanding of their treatment goals. They expect their healthcare providers to come up with an appropriate treatment strategy when they visit the doctor, and they often do not take their prescribed medications.

This stems from a lack of communication between healthcare providers and patients. If healthcare providers fully explained the need for medication, the goals of treatment, and the level of risk of cardiovascular events, and patients understood this, adherence would be higher. If patients felt uncomfortable with the medication or experienced problems while taking it, they could have discussed it with their healthcare provider and reoriented their treatment to reach their treatment goals ultimately. Since the primary goal of treatment is to prevent cardiovascular events, it is critical that patients adhere to their medications and not discontinue them without discussion due to a lack of understanding of the disease.

Studies have shown that adherence to treatment goals tends to be lower as patients move into higher-risk groups. 60-70 percent of ultrahigh—and high-risk patients require additional LDL-C management, and this is where Leqvio's role will become even more critical. Treatment adherence is as essential as efficacy to further lower LDL-C levels. Leqvio's ability to provide effective and sustained LDL-C control with twice-yearly dosing may provide a more robust benefit in this patient population.

Many studies have repeatedly shown that poor patient adherence is associated with uncontrolled LDL-C and poor prognosis. Therefore, it is essential to select the optimal drug, develop a treatment strategy, and regularly monitor the drug to assess its effectiveness and adherence. In addition, it is essential to improve patient adherence to treatment based on close communication with healthcare providers.

Q: We heard that the first prescriptions have been made since Leqvio's launch in Korea. Given that Leqvio is a non-reimbursed option and there are other reimbursed options, such as PCSK9 inhibitors, what were the criteria for prescribing Ldqvio?

A: To date, we have prescribed Leqvio in three cases, all in patients with acute myocardial infarction (AMI). All of them were at very high risk of cardiovascular events, with blood tests performed in the emergency department showing very high LDL-C levels above 200 mg/dL, and one patient, who was later diagnosed with familial hypercholesterolemia (FH), had LDL-C levels of 368 mg/dL and total cholesterol levels above 460 mg/dL.

Leqvio may not be appropriate for every patient. In this case, however, the patient had developed ASCVD and had very high LDL-C levels, making Leqvio a good candidate. In general, guidelines recommend high-dose statins, followed by ezetimibe if they are ineffective, and PCSK9 inhibitors should be considered if LDL-C is not effectively controlled despite combination therapy. However, high-dose statins and ezetimibe do not provide much scope for LDL-C reduction in patients with very high LDL-C levels. For example, if you prescribe a high-dose statin to a patient with an LDL-C level of 200 mg/dL or higher, you can expect a 40-45 percent LDL-C reduction and about a 50 percent reduction with ezetimibe. In the end, patients are still at risk of recurrent cardiovascular events because it is difficult to get LDL-C below 100 mg/dL.

If we follow the order of statin, ezetimibe, and PCSK9 inhibitors according to guidelines and reimbursement criteria, it delays the timing of treatment and takes a significant amount of time to achieve a sufficient therapeutic benefit. Therefore, if the LDL-C level is above 200 mg/dL, it is obvious that it will be difficult to reach the expected level even with a high-dose statin or ezetimibe combination. So, it is necessary to discuss treatment strategies with patients and explain effective treatment strategies and reimbursement criteria for each treatment to lower LDL-C quickly.

I explain that in the domestic reimbursement environment, some PCSK9 inhibitors are covered by insurance when used after statin and ezetimibe combination therapy and that Leqvio is convenient because it is self-injectable and can be taken every six months, but it is not reimbursed. Patients may choose Leqvio if they want aggressive therapy and can afford it. This is especially true for older adults, who may not be as adherent and may prefer to have Leqvio administered by a healthcare provider in the hospital rather than self-injecting.

Q: Why is it necessary to lower LDL-C so rapidly in patients who have had an acute cardiovascular event, such as an acute myocardial infarction?

A: Elevated LDL-C levels do not necessarily predict recurrent cardiovascular events, but the risk is certainly there. Studies have repeatedly shown that patients who present with an early myocardial infarction have an increased risk of recurrent cardiovascular events. Some studies have reported that the risk can be as high as 10 percent. Of course, with the recent development of effective treatments and more potent antiplatelet drugs, the risk of recurrent cardiovascular events has decreased, but there are still risk factors that need to be addressed early and aggressively.

Although LDL-C targets are more closely monitored and controlled in teaching hospitals, not all healthcare providers regularly check their patients' LDL-C levels. Some providers may be inclined to continue treatment with the initial medication prescribed. While it is important to check whether a patient has achieved their LDL-C goal (70 mg/dL or 55 mg/dL or less) and adjust their medication if necessary, this process can sometimes be omitted, resulting in therapeutic inertia. In other words, repeated and regular monitoring and subsequent changes in treatment strategy are not feasible in the local practice setting. Given these realities, effective and rapid LDL-C control from the outset can significantly benefit patients. Patients may want to consider treatment options, such as Leqvio, which is highly adherent and effective in reducing LDL-C.

Q: You're just starting to prescribe Leqvio, but you've prescribed PCSK9 inhibitors many times before. Have they experienced any adverse events or particular problems with them?

A: Historically, statins have long been the primary lipid-lowering therapy (LLT) option. Recently, the LLT paradigm has been rapidly changing with the advent of non-statin therapies, including ezetimibe, PCSK9 inhibitors, and siRNA therapies. Most cardiologists agree that non-statin agents are relatively free of adverse events compared to statins.

For example, ezetimibe may have reported adverse events, including abdominal discomfort, but this is one of the milder side effects. Minor adverse events can accelerate the disease process in patients who accumulate bad cholesterol by not using the drug, so the question is, "Can the drug achieve what you want it to achieve? It is necessary to comprehensively evaluate the drug's therapeutic benefit and the risk of adverse events.

Notably, PCSK9 inhibitors are relatively free from adverse events. In the case of Leqvio, injection site adverse events are commonly reported, which are not considered serious adverse events and should not be a barrier to prescribing Leqvio.

Q: What about Leqvio's lipid-lowering effects? We’re curious to know if the studies' results are consistent.

A: Having prescribed Leqvio, the data from clinical studies and the actual clinical outcomes were somewhat different. Leqvio's treatment effect was even better at the actual practice site. Two weeks after prescribing Leqvio, I performed a blood test and found that the LDL-C reduction was stronger than expected. In two patients with LDL-C levels above 200 mg/dL who were treated with a high-dose statin and ezetimibe and subsequently prescribed Leqvio, I found that LDL-C levels dropped to 26 mg/dL and 29 mg/dL after 15 and 18 days of follow-up, respectively. While the clinical study showed a gradual decrease in LDL-C levels over a three-month period, the real-world experience was more rapid and decisive. If statins, ezetimibe, and Leqvio had been used sequentially, LDL-C levels would have decreased gradually after reaching 100 mg/dL.

Leqvio helps shorten the time to target LDL-C. Patients who have experienced a major cardiovascular event are still at risk for cardiovascular events, even with high doses of medication. Drugs like Leqvio can be considered a significant treatment option to reduce that risk, and I have seen its usefulness in real-world prescribing.

Q: What could be improved for effective LDL-C management for ASCVD patients in the country?

A: Most of all, the government must speed up Leqvio's reimbursement. While Leqvio is similar to other PCSK9 inhibitors that are reimbursed, it is different for clinicians who see patients in the clinic. While LDL-C management typically emphasizes “how much LDL-C target is lowered,” clinicians are most concerned with "how well LDL-C target is maintained in the long term. Leqvio has a strong track record of achieving LDL-C target levels and in treatment persistence, i.e., maintaining stable LDL-C over time.

Patient adherence is also a key consideration. High-risk patients with cardiovascular disease tend to have relatively low adherence. Adherence plays a big role in patient outcomes. Leqvio improves patient burden for self-medication by enabling LDL-C management in the clinic with a healthcare provider, and it is dosed initially every three months and then every six months, enabling effective LDL-C control in just two doses per year. These strengths significantly improve patient convenience and are expected to result in higher adherence and treatment persistence, ultimately positively impacting individual patient outcomes.

I expect positive results from Leqvio's cardiovascular outcome trials (CVOT) data. Given that Leqvio's mechanism of action is bound to produce significant results in CVOT, it is only a matter of time before it is approved for ASCVD. Leqvio's reimbursement is inevitable, and I hope to see improved access to treatment soon so that more patients can benefit from its treatment.