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Q&A on Targeting LDL-C
Expert Answers to Frequently Asked and Compelling Questions on Meeting LDL-C Targets

Released: May 10, 2024

Expiration: May 09, 2025

Michael Miller
Michael Miller, MD, FACC, FAHA
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Key Takeaways
  • Establishing and achieving treatment targets in hyperlipidemia management is essential for lowering a patient’s risk of major adverse cardiovascular events.
  • Healthcare professionals are continuously engaged in developing evidence-based and personalized treatment plans for their patients with hyperlipidemia using statin and nonstatin therapies.

In this commentary adapted from a live satellite symposium question and answer session, Michael Miller, MD, FACC, FAHA, answers frequently asked clinical questions about establishing and achieving patient-specific low-density lipoprotein cholesterol (LDL-C) targets, assessing lipoprotein (a) (Lp[a]) levels, and using statin and nonstatin therapies to optimize care in hyperlipidemia.

When you start nonstatin therapy, do you continue the statin so long as there is not a tolerability issue?

Michael Miller, MD, FACC, FAHA:
Yes, statins serve as our lipid-lowering foundation based on the wealth of clinical trial data consistently demonstrating their proven role in cardiovascular (CV) risk reduction.  Considerations for the use of nonstatin therapies such as ezetimibe, PCSK9 inhibitors (alirocumab, evolocumab, inclisiran), bempedoic acid, or bile-acid sequestrants as add-ons to statins or as monotherapy include lack of tolerability to the statin dose required for LDL-C target goal attainment, thereby necessitating a lower statin dose and/or statin intolerance, which is manifested primarily as statin-associated muscle symptoms (SAMS). 

Patients with SAMS will generally experience symmetric, bilateral muscle aches or pain, most likely affecting the proximal muscles, including the upper arms, chest, back, and thighs, rather than the lower arms and legs. For patients with SAMS, healthcare professionals (HCPs) should discontinue the statin and allow patients to washout these side effects over a 1- to 2-week period. Once symptoms absolve, my approach is to try another statin on a thrice-weekly (MWF) regimen. I find that patients love taking the weekend off from their statin and maintain sufficiently good LDL-C reduction (approximately 25%-35%). If patients need additional LDL-C reduction, one option is to try up-titrating the statin dose while continuing the MWF regimen and adding daily ezetimibe and/or a PCSK9 inhibitor as needed. 

Is there such a thing as lowering LDL-C too much? Can patients’ LDL ever be too low?

Michael Miller, MD, FACC, FAHA:
The short answer is no. When people are born, in the absence of a genetic abnormality such as familial hypercholesterolemia, their LDL-C is approximately 25 mg/dL, with levels increasing to 60-70 mg/dL by the age of 4 years. This is the level that HCPs view as physiologic, as LDL-mediated cholesterol plaques do not form until LDL-C levels exceed these values. Not surprisingly, recent guideline updates in the United States and Europe now support driving LDL-C levels below 55 mg/dL in the highest-risk patients. However, HCPs do not advocate initiating pharmacotherapy to achieve that level globally.

This question is often asked, especially since the advent of PCSK9 inhibitors, as they have ushered in the possibility of lowering LDL-C to levels we have not previously attained. For example, in the FOURIER trial, the on-treatment LDL-C level of participants receiving evolocumab reached a median of 30 mg/dL, which was maintained over time, and there were patients that got down even into the single digits. In the past, HCPs thought that very low LDL-C levels would adversely affect cell membranes and cognitive function. However, a subgroup analysis of FOURIER called the Ebbinghaus trial did not identify cognitive deficits following formal neurocognitive testing in patients with low LDL-C assigned to statins and the PCSK9 inhibitor, evolocumab. Furthermore, a post-hoc analysis of FOURIER reported that patients with the lowest LDL-Cs continued to experience CV benefit without increasing adverse effects. In comparison to years prior, when HCPs would back off statin therapy if LDL-C levels dropped below 40 mg/dL, current evidence suggests that on-treatment LDL-C levels below 30 mg/dL are acceptable and can be maintained if therapies are well tolerated.

Do you order advanced lipoprotein testing to evaluate particle size or particle number? If so, in what patients would you order these?

Michael Miller, MD, FACC, FAHA:
The clinical outcome studies have not sufficiently examined the extent to which LDL-C subfractionation or ApoB perform as predictors of CV risk, compared to LDL-C levels. However, non-HDL cholesterol (total cholesterol minus HDL cholesterol) has been shown to perform as well as ApoB and is included in the lipid panel. To minimize costs for my patients, I keep it simple and just order a lipid panel. In addition to including advanced measurements in research studies, the only other scenario where I might consider specialized lipoprotein testing is when LDL-C levels and risk factors are in the borderline range for treatment. However, in these cases, the 2018 American College of Cardiology/American Heart Association guidelines place higher emphasis on obtaining a coronary calcium score to help guide therapeutic decision-making.

Given the evidence that Lp(a) is associated with CV risk but with the current lack of approved Lp(a) therapies, what would you do for a patient today who had a premature event with a documented elevation in Lp(a)?

Michael Miller, MD, FACC, FAHA:
Lp(a) levels are genetically determined and unfortunately, are not sufficiently improved upon with lifestyle modifications such as diet and/or exercise. The prevalence of elevated Lp(a) is high, with approximately 20% to 25% of patients with a history of CV disease demonstrating high Lp(a) levels, defined as ≥50 mg/dL or ≥125 nmol/L.  In high-risk patients with elevated Lp(a), the current goal is to lower LDL-C levels because the combination of elevated Lp(a) and LDL-C raises CV risk to a greater extent than elevation in either of these lipoproteins alone. Fortunately, there are very powerful Lp(a)-reducing therapies being tested, including pelacarsen, lepodisiran, and olpasiran.  In the meantime, and until results of clinical outcome trials become available, PCSK9 inhibitors can be used because they lower Lp(a) levels by approximately 25%. However, bear in mind that because no FDA-approved indication exists, the cost of this medication will be left to the self-paying patient rather than the respective healthcare insurer.

Your Thoughts?
Which nonstatin therapies do you prescribe to help patients meet their lipid-lowering goals? Leave a comment to join the discussion!

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How often do you order an Lp(a) when assessing ASCVD risk in your practice?

2.

Which of the following nonstatin therapies do you prescribe to help patients meet their lipid-lowering goals? (Choose all that apply) 

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