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Closing Gaps in LDL-C Control: Treatment Intensification and Emerging PCSK9 Options

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Released: October 30, 2026

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Despite advances in lipid-lowering therapies, many patients with atherosclerotic cardiovascular disease remain above recommended LDL-C thresholds, increasing their risk of cardiovascular events. Explore evidence supporting timely treatment intensification, strategies for overcoming barriers to LDL-C goal attainment, and the evolving role of PCSK9-targeted therapies in optimizing lipid management and reducing cardiovascular risk.

Ty J. Gluckman
Ty J. Gluckman, MD, MHA
Timely LDL C Treatment Intensification

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Despite the availability of effective lipid-lowering therapies, gaps in low-density lipoprotein cholesterol (LDL-C) monitoring and treatment intensification continue to leave patients with atherosclerotic cardiovascular disease (ASCVD) at increased cardiovascular risk. In this commentary, Ty J. Gluckman, MD, MHA, discusses the importance of reducing cumulative LDL-C exposure, strategies for individualizing lipid-lowering therapy, and how emerging PCSK9-targeted therapies may help address persistent barriers to LDL-C goal attainment.

Despite the availability of highly effective lipid-lowering therapies, many patients with ASCVD remain above recommended LDL-C thresholds. In your experience, what are the biggest reasons healthcare professionals (HCPs) are not achieving optimal LDL-C control, and what concerns you most about these missed opportunities?
We see consistently across multiple studies opportunities to improve LDL-C lowering in patients with clinical ASCVD. I will start by saying that it is a challenge to adequately achieve LDL-C goals if you do not measure one's lipids. In 2018 and again in 2026, there was a recommendation that, in individuals who have not yet achieved their LDL-C goal, treatment intensification is warranted, and a repeat lipid panel is warranted 4-12 weeks later. Once patients have achieved their LDL-C goal, a lipid panel is warranted every 6-12 months, primarily to monitor for adherence to therapy.

Ultimately, if you are not measuring lipids, either as part of treatment intensification or as part of maintaining people on therapy, you miss an opportunity to adjust one's treatment regimen to ensure that they are at goal. The other piece of this is that there are multiple therapies that we have available on a backdrop of intensive lifestyle changes. We know from multiple observational studies and registries that statin therapy is underused, high-intensity statin therapy is underused, and multiple nonstatin therapies, including drugs like ezetimibe and PCSK9 inhibitors, are underused.

We often focus on a patient's current LDL-C level. However, recent evidence highlights the cumulative impact of LDL-C exposure over time. How should this understanding influence treatment decisions, particularly for patients who are already receiving lipid-lowering therapies?
We are increasingly keen about LDL-C, or cholesterol more generally, exposure, analogous to the way that we have thought of tobacco exposure. Historically, we have assessed tobacco exposure as pack-years: how many packs of cigarettes a person smoked and for how many years. Looking at cumulative exposure, or an area under the curve, cholesterol is really no different. A significantly heightened level of LDL-C may require a shorter duration of exposure to increase cardiovascular risk compared with someone who has an elevation of their LDL-C, but not to the same degree, for which a longer time horizon of exposure is needed to put people at sufficient risk to have cardiovascular events.

For individuals who are currently receiving lipid-lowering therapy, it is important for the future to bring their LDL-C to goal to minimize the risk of adverse cardiovascular events. But this really underscores the importance, in those individuals who are at increased cardiovascular risk, of early recognition of those risk factors early in life. There is the potential for individuals with the most severe forms of elevated LDL-C, and even lesser degrees of elevation of LDL-C if their risk demands it, to get on lipid-lowering therapy on top of intensive lifestyle changes to reduce that cumulative exposure over the course of one's lifetime. Ideally, this helps to minimize their risk of incurring a cardiovascular event down the road.

Consider a patient with established ASCVD whose cholesterol levels remain above the recommended threshold despite a maximally tolerated statin. How do you approach the decision to intensify treatment, and when should an internal medicine or family medicine provider consider agents such as PCSK9-targeted therapies?
First and foremost, I would say that beyond LDL-C, non–high-density lipoprotein (HDL-C) and, in select patients, measurement of apolipoprotein B can be helpful in more accurately gauging or assessing their atherogenic risk. In the scenario where patients do not have LDL-C, non-HDL-C, and apolipoprotein B levels at the desired goal, the question is: What should be done next? If they are on maximally tolerated statin therapy, then we look to nonstatin therapy. Before we go there, if patients are not on statin therapy or is not at the maximally tolerated formulation of statin therapy, the first priority would be intensifying their statin regimen to maximize LDL-C reduction.

Once that is achieved, the guidelines recommend 2 approaches as being reasonable and informed by cardiovascular outcomes trial data. The first option is the addition of ezetimibe, with or without concomitant use of bempedoic acid. These are 2 oral nonstatin therapies that, in combination, can achieve potentially 35% or greater LDL-C reduction for a given individual. An alternative is to use a PCSK9 inhibitor that is a monoclonal antibody, such as evolocumab and alirocumab, because they have cardiovascular outcomes trial data supporting their use. The PCSK9 inhibitor monoclonal antibodies in general will achieve a 45%-64% reduction in LDL-C.

We generally reserve other nonstatin LDL-C–lowering agents as being at a next tier below these options, either ezetimibe with or without bempedoic acid vs a PCSK9 inhibitor monoclonal antibody, because other nonstatins at this moment do not have cardiovascular outcomes trial data to support their use and substantiate cardiovascular event reduction.

The decision between ezetimibe with or without bempedoic acid or a PCSK9 inhibitor depends in part on how far they are from their LDL-C goal. A patient who is more than 20% to 25% away from their goal is unlikely to achieve getting to goal on ezetimibe alone. A patient who is 50% or more above their goal is unlikely to achieve that effect with a drug like ezetimibe with bempedoic acid, in which case a PCSK9 inhibitor monoclonal antibody would be favored. Informing this also is coverage, affordability, and access to some of those therapies, acknowledging that ezetimibe is generic. Bempedoic acid and the PCSK9 inhibitor monoclonal antibodies are not yet available in generic formulation. Finally, this is all driven by shared decision-making. Ezetimibe and bempedoic acid are oral, and the PCSK9 inhibitor monoclonal antibodies are injectable, so that too may inform treatment decision-making by the prescribing HCP and, in particular, by the patient.

Clinical inertia is not always driven by a lack of clinical knowledge. Practical barriers may affect the use of PCSK9 inhibitors. In your experience, which barriers most affect their use, and what strategies have helped overcome them?
The PCSK9 inhibitor monoclonal antibodies were first approved by the FDA in mid-2015. Early on, payer denial rates were extremely high, and the drugs were associated with high out-of-pocket patient costs. Now, the treatment landscape, access, and affordability of the PCSK9 inhibitor monoclonal antibodies have substantially improved, such that most of my patients who are appropriate for therapy can get authorized for therapy and afford the out-of-pocket cost associated with their use.

Reasons why PCSK9 inhibitor monoclonal antibodies may not be used as often as they could and should may relate to hesitation by an HCP who remembers a decade ago when getting these drugs approved and made available to patients was much more challenging. It also may relate to an HCP’s comfort level in prescribing an injectable agent for LDL-C lowering. From a patient perspective, this also may relate to the challenge of being on one more medication, an injectable formulation, and potential out-of-pocket cost limitations for the drug.

Again, my experience suggests that most patients eligible for therapy can get authorized, and for most patients who are eligible for therapy, it is generally affordable. Time has allowed many of those barriers to adoption to be overcome. That being said, there are potential ongoing challenges. I would say the availability of newer agents, for example, the first FDA-approved oral PCSK9 inhibitor, even though there is not yet a cardiovascular outcomes trial available, is associated with a very meaningful reduction in LDL-C level that parallels that of the monoclonal antibodies and has an oral formulation that may make this accessible to individuals who are hesitant or resistant to taking an injectable agent.

The PCSK9 therapeutic landscape continues to evolve with new approaches, such as oral delivery and alternative injectable formulations. Which developments do you find most promising, and how might they address the limitations you just mentioned?
There are 3 FDA-approved PCSK9 inhibitors in addition to the PCSK9 inhibitor monoclonal antibodies alirocumab and evolocumab. These 3 newer agents have been available for varying degrees of time. The oldest of those agents that do not yet have cardiovascular outcomes trial data is inclisiran, which is a small interfering RNA molecule that has the advantage of every-6-month dosing after the first 2 doses. The drug is administered in healthcare settings. For patients insured under Medicare, this is covered as a medical benefit under Medicare Part B, not as a pharmacy benefit under Medicare Part D. So the advantages are there may be a differential out-of-pocket cost for a given patient, and the drug is not self-administered for patients in whom that is a concern. Finally, from a clinical perspective, we know that individuals have taken the drug based on the fact that it is required to be administered in a healthcare setting.

There are 2 other PCSK9 inhibitors that have been approved by the FDA much more recently. The first of those is the drug lerodalcibep, which is a PCSK9 inhibitor that is dosed and self-administered monthly. We do not have cardiovascular outcomes trial data lerodalcibep. The other drug is enlicitide, which is the first oral PCSK9 inhibitor. Both of these drugs, not unlike inclisiran, are able to achieve very meaningful reductions in LDL-C that are similar to those achieved with the monoclonal antibodies.

We are awaiting cardiovascular outcomes trial data for some of these newer PCSK9 inhibitors. Based on the decades of experience treating patients with LDL-C–lowering agents, I come with an expectation that drugs that can meaningfully lower LDL-C will translate into cardiovascular event reduction. But we do not yet have outcomes data for inclisiran, lerodalcibep, or enlicitide, and I look forward to reviewing that data once they are available.

If you could recommend 3 changes that HCPs could implement in their practice tomorrow to improve cholesterol goal attainment and reduce residual cardiovascular risk, what would those recommendations be?
I would say, first and foremost, you cannot treat what you do not measure. So consistent measurement of LDL-C every 4-12 weeks after initiation of drug therapy, changing the dose of a drug, or initiation of additional drug therapy is important to assess whether someone has achieved their LDL-C goal, and reassessment of one's lipids, in particular LDL-C, every 6-12 months after to ensure that the patient is adherent to therapy.

Second, cumulative evidence over decades has demonstrated that lower LDL-C levels are associated with a lower risk for adverse cardiovascular events. Therefore, because lower is better, intensifying one's LDL-C–lowering regimen on top of maximally tolerated statin therapy by adding 1 or more nonstatin therapies can help to achieve one's LDL-C and non-HDL-C goals, but more important than that, it can help to achieve cardiovascular event reduction.

Third, recognize that although early experience with PCSK9 inhibitor monoclonal antibodies was challenged by high payer denial rates and affordability, the landscape has substantially changed over the last 11 or more years. Today, most eligible patients are able to get authorization of PCSK9 inhibitor monoclonal antibodies and afford them. In addition, the totality of evidence has grown such that we now see data supporting cardiovascular event reduction in secondary prevention patients who have not had a prior heart attack or stroke and in patients with diabetes at increased cardiovascular risk. So we have a broader patient population that is eligible for such therapy based on more recent trial data.

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How confident are you in intensifying treatments for patients with ASCVD who do not achieve targeted LDL-C levels?

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