Transcript
Announcer:
Welcome to ReachMD. This medical industry feature is titled Aiming to Stay Lower for Longer: Exploring the Clinical Evidence for Long-Term LDL-C Reduction.
Dr Freeman:
Hello, and welcome to today’s podcast. This program is sponsored by Novartis Pharmaceuticals Corporation and is intended for US health care professionals. We’ve been compensated by Novartis Pharmaceuticals Corporation for our time.
I’m Dr Andrew Freeman, a cardiologist and Director of Cardiovascular Prevention. Today, we’ll explore strategies for LDL-C management, focusing on helping patients with atherosclerotic cardiovascular disease, or ASCVD, and hypercholesterolemia reach and maintain their low-density lipoprotein C, or LDL-C, target. Many of us were trained to believe that statins were the only answer, but we now have nonstatin LDL-C–lowering treatment options available for patients requiring additional LDL-C reduction. We will take a closer look at the importance of timely action in LDL-C management and its impact on long-lasting LDL-C reduction, all brought to life through a patient journey that will likely resonate with your own clinical experience.
And I am delighted to be joined today by Dr Lily Dastmalchi.
Dr Dastmalchi:
Thank you for having me! I’m Dr Lily Dastmalchi, Assistant Professor of Medical Education and a preventive cardiologist with particular interest in women's cardiovascular and cardio-metabolic health, including cardio-obstetrics and menopausal health. I'm looking forward to discussing the proactive approach to LDL-C management that should be taken for all patients with ASCVD, regardless of prior cardiovascular, or CV, events.
Dr Freeman:
Before we begin today’s discussion, let’s review the indication for LEQVIO.
LEQVIO (inclisiran) injection is indicated as an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH).1 LEQVIO can be a valuable tool to support appropriate patient types with elevated LDL-C. You may choose to prescribe it as a standalone option or concomitantly with a statin dose that you deem appropriate for your individual patients.1
Okay, well let’s get down to it. How can we optimize LDL-C management earlier versus assuming a ‘wait-and-see’ approach? To explore this, we’ll follow John, a hypothetical patient, along 2 possible treatment paths and examine how different strategies shape long-term LDL-C management.
Let's walk through a patient case scenario. While this is a hypothetical situation, the experience is consistent with what we both have encountered often in our practices. Consider John, a 65-year-old White male. Looking at his lab results, his LDL-C level is 130 milligrams per deciliter, despite being on a 20-milligram dose of rosuvastatin. This is a crucial point—even with treatment, he's not at LDL-C target. Beyond the elevated LDL-C, he presents with several other CV risk factors. He has type 2 diabetes. He's obese, with a body mass index of 31. And he has sleep apnea. Given his symptoms and high coronary calcium, or CAC score, a coronary computed tomography angiogram, or CCTA, is ordered. The results confirm the presence of ASCVD.
What we commonly see in clinical practice for patients like John—those diagnosed with ASCVD but without a history of a cardiovascular event—is that clinicians often decide to escalate statin therapy to maximally tolerated dose. So, let’s say John’s clinician made this decision, and his statin dose was increased. Soon after, John reports side effects, which he attributes to the statin. At his next appointment, a few months later, his LDL-C is hovering around 105 milligrams per deciliter, signaling an opportunity to consider a change in LDL-C management approach to help him reach and maintain goal. However, in clinical practice, many patients like John remain on statin therapy alone, even when additional LDL-C lowering is warranted.2,3 Evidence from clinical trials further confirm this gap, showing limited utilization of LDL-C–lowering treatments beyond statins, which can leave patients with elevated LDL-C.3,4
Dr Dastmalchi:
I think many clinicians overestimate the additional LDL-cholesterol reduction achieved by increasing the statin dose. Data show small incremental benefit from going from a moderate to a high-intensity statin.5,6 Moreover, studies have shown that, even with a maximally tolerated statin, many patients with ASCVD struggle to achieve LDL-C target.5,7 Several studies, including GOULD, which was a prospective observational registry study that included more than 5000 patients, have shown that LDL-C–lowering therapy is rarely intensified for patients with ASCVD who do not meet their LDL-C goals.2
So, coming back to John—with his LDL-C stuck around 105 milligrams per deciliter —it can feel frustrating for both the patient and the physician when LDL-C levels remain above target. Is statin therapy enough for this patient? In my opinion, and increasingly in the field, the answer is a resounding no.
Dr Freeman:
The challenge we face, and I think many of us can agree on this, is that patients sometimes remain at elevated LDL-C levels for extended periods. This highlights the importance of proactively managing LDL-C in individuals who are diagnosed with ASCVD but who have not yet had a cardiovascular event. In alignment with current guidelines that emphasize aggressive LDL-C lowering, clinicians should proactively plan for the next step in therapy for patients who remain above LDL-C goal despite statin optimization.
Dr Dastmalchi:
Absolutely. In my practice, it is very important for me and our care team to achieve sustained LDL-cholesterol reduction from the outset. When managing LDL-cholesterol, my decisions are tailored to the patient's unique profile, including their medical history, how quickly we need to achieve LDL-C reduction, and patient preference. In patients with an elevated LDL-cholesterol, I use CAC score per guidelines to further refine risk assessment and inform treatment choices.
Now, let’s rewind and consider this approach to get John’s LDL-cholesterol levels to recommended targets. Instead of solely relying on statin escalation, what if we had introduced a nonstatin therapy like LEQVIO earlier on?
Dr Freeman:
We don’t necessarily have to treat our patients with statins first before considering LEQVIO.1 For patients with LDL-C levels exceeding 100 milligrams per deciliter, I consider LEQVIO from the outset, either in conjunction with an appropriate statin dosage or as a standalone therapy, where appropriate, based on specific patient factors. Data from pivotal trials provide compelling evidence of its efficacy and safety in patients with ASCVD.1,8,9 For those who may not be as familiar with the LEQVIO clinical data, could you highlight the pivotal trial results that made you sit up and take notice?
Dr Dastmalchi:
Absolutely. The ORION-10 and ORION-11 pivotal trials evaluated the efficacy and safety of LEQVIO in patients with elevated LDL-C and established ASCVD or increased risk of cardiovascular disease, or CVD.8 Patients were randomized 1:1 to receive subcutaneous injections of LEQVIO 284 milligrams or placebo in addition to their maximally tolerated statin therapy on Days 1, 90, 270, and 450.1 Patients were on maximally tolerated statin, with or without ezetimibe, and still required additional reduction to get to LDL-C target. Other nonstatin therapies were excluded in these trials8. The primary efficacy measure was the percentage change in LDL-cholesterol from baseline to Day 510.8
From the ORION-10 clinical trial, we saw that LEQVIO demonstrated powerful and consistent LDL-C reduction throughout each 6-month dosing interval, with a 52% difference in LDL-C reduction from baseline compared to placebo at Month 17.8 Additionally, in ORION-10, 84% of patients with ASCVD who were treated with LEQVIO achieved LDL-C levels less than 70 milligrams per deciliter at Month 17 compared with 18% of patients treated with placebo.10 As for the results from ORION-11 that included patients with elevated LDL-C with ASCVD or an increased risk of ASCVD, they were consistent with ORION-10.8,11
Dr Freeman:
Those are encouraging results indeed. In my clinical practice, we consider LEQVIO for patients with established ASCVD— those who’ve experienced events such as myocardial infarction and stroke or have undergone revascularization. In addition, I also consider LEQVIO for my patients that are at an increased risk of ASCVD who have elevated LDL-C along with other factors including HeFH, type 2 diabetes, or a 10-year risk of a cardiovascular event of 20% or greater.8 The clinical data supports the efficacy and safety of LEQVIO in these populations.8
Dr Dastmalchi please tell us about your clinical experience with LEQVIO in managing patients with ASCVD or increased risk of CVD?
Dr Dastmalchi:
I've found LEQVIO to be a great addition to my treatment armamentarium. My patients generally tolerate it well, and the LDL-cholesterol reduction I've seen in my patients has been in line with what was seen in clinical trials. My patients have reported that the twice-yearly dosing after the 2 initial doses administered by a health care professional is convenient for them.
It’s also important to highlight the long-term data from the ORION-8 trial, which examined the durability of LDL-C reduction with LEQVIO and additional safety data with extended use.9 ORION-8, a long-term extension study, was designed to assess the long-term efficacy, safety, and tolerability of LEQVIO with up to 3 years of follow-up in more than 3000 patients with ASCVD, increased risk of ASCVD, or heterozygous FH.9
The primary end points were proportion of patients achieving pre-specified LDL-C goals at the end of the study and safety.9 The end of the study was defined as day 1080 or greater than or equal to 90 days after the last LEQVIO dose.9 The key secondary end point was the percentage change in LDL-C level from baseline to the end of the study.9 Limitations of the study include that it was not blinded or controlled, and it included inherent self-selection bias for continuing onto the extension trial. The open-label design and absence of a control group may present difficulties in the interpretation of the results, allowing comparisons only to baseline values.9
Dr Freeman, we’ve seen promising results from the pivotal trials, but as you know, long-term data can tell a different story. With that in mind—how do the results from ORION-8 stack up? Do they reinforce what we saw earlier?
Dr Freeman:
Results from ORION-8 were consistent with ORION-10 and ORION-11.9 Approximately 80% of patients achieved target LDL-C levels.9 Also, there was an approximately 50% reduction in LDL-C levels at the end of the study.9 The long-term results for LEQVIO are reassuring. The consistent LDL-C reduction observed in clinical trials aligns with what I’ve seen in my own practice—it’s a therapy that, in my experience, has worked well for patients who need that additional LDL-C lowering. These data are critical for building confidence in using LEQVIO for long-term LDL-C management.1,9
Now, let’s take a look at the safety data for LEQVIO from these trials. How does the safety profile of LEQVIO help make the case for its use in patients like John?
Dr Dastmalchi:
That’s a great question. From the Phase 3 clinical trials over 18 months, the most common adverse reactions occurring in greater than or equal to 3% of patients treated with LEQVIO, and more frequently than placebo, were injection site reaction, arthralgia, and bronchitis.1,8 Adverse reactions leading to discontinuation occurred in 2.5% of patients treated with LEQVIO vs the 1.9% of patients receiving placebo.1 Injection site reactions were the most common cause for treatment discontinuation, observed in 0.2% of patients taking LEQVIO versus 0% taking placebo.1 The majority of adverse events were mild to moderate.8 In ORION-8, long-term safety data beyond 6 years was consistent with the Phase 3 trials. LEQVIO was well tolerated, and there were no new safety signals.9 This well-tolerated safety profile is crucial for ensuring patients can stay on the treatment long term to help achieve and maintain LDL-cholesterol reduction.9 But the best therapy is the one that patients actually take. You may have patients with elevated LDL-cholesterol who struggle with their medication schedules, especially if they’re looking at 12 or 26 yearly self-injections of PCSK9 monoclonal antibodies.12,13 LEQVIO, on the other hand, is HCP-administered with twice-yearly dosing after the initial 2 doses.1
So, Dr Freeman, how do you discuss the dosing and administration of LEQVIO with your patients?
Dr Freeman:
I focus on 3 key points. First, I explain that it’s a subcutaneous injection, and after the initial 2 doses, it’s only needed twice a year. Patients are often relieved to hear that. Secondly, I also clarify that LEQVIO may be an option to help lower LDL-C, whether or not they are currently taking a statin. And finally, to further simplify things, I let them know that we can often coordinate the injection with their routine appointments, making it easier to stay on track with their treatment.
Dr Dastmalchi:
Additionally, knowing that the LDL-C reduction is sustained over each 6-month dosing interval, with a well tolerated safety profile that is consistent with that seen in the pivotal trials, gives us the confidence to recommend LEQVIO for long-term LDL-cholesterol management.9 Looking back at our hypothetical patient John, I’d prefer to promptly initiate a nonstatin like LEQVIO because the approach of sequential statin adjustments can lead to significant delays in achieving target LDL-cholesterol levels.
Any last thoughts from you Dr Freeman?
Dr Freeman:
The evidence is clear: By being proactive and aggressive with LDL-C lowering early on, we may be able to get our patients to their LDL-C targets sooner.14,15 And with therapies like LEQVIO, which offer a well-tolerated safety profile and a twice-yearly dosing schedule, we have the potential to achieve long-lasting LDL-C reduction.1,9
Dr Dastmalchi:
That brings us to the close of today’s program. Thank you, Dr Freeman, for this insightful discussion.
Dr Freeman:
Thank you, Dr Dastmalchi, and thank you for listening.
Announcer:
For more information about LEQVIO, please visit CVPerspectives.com.
Voiceover:
IMPORTANT SAFETY INFORMATION
Contraindication: LEQVIO (inclisiran) is contraindicated in patients with a prior serious hypersensitivity reaction to inclisiran or any of the excipients in LEQVIO. Serious hypersensitivity reactions have included anaphylaxis and angioedema.
Hypersensitivity Reactions: Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported in patients treated with LEQVIO. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct patients to seek medical attention promptly.
Adverse Reactions: Adverse reactions in clinical trials (≥3% of adult patients treated with LEQVIO and more frequently than placebo) were injection site reaction, arthralgia, and bronchitis.
Please see LEQVIO full Prescribing Information available on this site or at LEQVIOHCP.com.
Dr Freeman:
Important Safety Information for LEQVIO is available underneath the player of this audio presentation.
Announcer:
This program was sponsored by Novartis Pharmaceuticals Corporation. If you missed any part of this discussion, visit ReachMD.com/Industry-Feature. This is ReachMD. Be Part of the Knowledge.
References:
- Leqvio. Prescribing information. Novartis Pharmaceuticals Corp.
- Cannon CP, de Lemos JA, Rosenson RS, et al. Use of lipid-lowering therapies over 2 years in GOULD, a registry of patients with atherosclerotic cardiovascular disease in the US. JAMA Cardiol. 2021;6(9):1060-1068.
- Data on file. Novartis Pharmaceuticals Corp; 2025.
- Knowlton KU, Navar AM, Anderson JL, et al. LDL-C management with inclisiran plus usual care vs usual care alone in participants with recent acute coronary syndrome: VICTORION-INCEPTION. Presented at: National Lipid Association’s 2025 Annual Scientific Sessions; May 29-June 1, 2025; Miami, FL.
- Rao SV, O'Donoghue ML, Ruel M, et al. 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2025;151(13):e771-e862.
- Ben-Yehuda O. Combination therapy with lower statin dose and the race to LDL-C goal: a clear winner? J Am Coll Cardiol. 2023;82(5):411-413.
- Wong ND, Young D, Zhao Y, et al. Prevalence of the American College of Cardiology/American Heart Association statin eligibility groups, statin use, and lowdensity lipoprotein cholesterol control in US adults using the National Health and Nutrition Examination Survey 2011-2012. J Clin Lipidol. 2016;10(5):1109-1118.
- Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020;382(16):1507-1519.
- Wright RS, Raal FJ, Koenig W, et al. Inclisiran administration potently and durably lowers LDL-C over an extended-term follow-up: the ORION-8 trial. Cardiovasc Res. 2024;120(12):1400-1410.
- Data on file. ORION-10 Clinical Study Report. Novartis Pharmaceuticals Corp; 2019.
- Data on file. ORION-11 Clinical Study Report. Novartis Pharmaceuticals Corp; 2019.
- Repatha. Prescribing information. Amgen Inc.
- Praluent. Prescribing information. Regeneron Pharmaceuticals, Inc.
- Blumenthal RS, Morris PB, Gaudino M, et al; Writing Committee Members. 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of dyslipidemia: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2026;153:e1-e123. Published online March 13, 2026. doi:10.1161/CIR.0000000000001423
- Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459-2472.
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