When statins aren’t enough: choosing injectable cholesterol medication

PCSK9 inhibitors are powerful injectable cholesterol medications—reducing LDL by 40–60% on their own and 50–60% when used alongside statins. They’re typically used for high-risk patients who remain above LDL targets despite standard therapy. 
Some patients can't tolerate statins, some are living with familial hypercholesterolemia, others simply can't reach LDL targets despite maximum statin therapy. For these patients, treatment escalation to an injectable cholesterol medication—a PCSK9 inhibitor—may be the right decision.

In this lesson from our Hyperlipidemia Essentials course, learn how to:

• Explain the PCSK9 inhibitor mechanism of action
• Identify which patients may benefit from PCSK9 inhibitor therapy
• Choose which PCSK9 inhibitor is right for your patient based on dosing and adherence considerations
• Recognize expected side effects and identify which are extremely rare
• Consider practical challenges related to cost, insurance approval, and adherence

Injectable cholesterol medication: PCSK9 inhibitors

[0:00]
Statins have been a cornerstone for managing hyperlipidemia for over 30 years, but newer options like PCSK9 inhibitors have expanded treatment possibilities, particularly for high risk patients who don't meet LDL targets with statins and ezetimibe. 
PCSK9, which stands for proprotein convertase subtilisin/kexin type 9 is an enzyme that plays a crucial role in cholesterol metabolism. Before diving into how PCSK9 inhibitors work, let's quickly review normal lipoprotein metabolism.

Lipoprotein metabolism

[0:36]
The liver expresses LDL receptors to remove LDL particles from the blood, recycling their cholesterol for uses like bile acid synthesis. Like a warehouse restocking its inventory, the liver expresses more LDL receptors as its LDL stores are depleted, allowing it to scavenge more LDL from the bloodstream. 

The role of PCSK9 in LDL receptor degradation

[1:01]
Now let's talk about PCSK9 itself. It's an enzyme that controls the number of LDL receptors on liver cells. More LDL receptors means less LDL in the blood. PCSK9 binds to an LDL receptor without interfering with LDL particle binding. Once an LDL particle attaches, the entire complex is internalized. Inside the liver cell, the LDL particle is released from the LDL receptor, and its cholesterol is processed normally. But in the presence of PCSK9, the LDL receptor is directed to a lysosome for degeneration, instead of being recycled. As a result, fewer LDL receptors are available to remove LDL from the blood, increasing LDL cholesterol levels in the bloodstream.

How PCSK9 inhibitors lower LDL cholesterol

Types of PCSK9 inhibitors

[1:54]
An imbalance in PCSK9 activity can make managing high cholesterol challenging. This is where PCSK9 inhibitors shine. There are different ways to inhibit PCSK9, including monoclonal antibodies such as evolocumab and alirocumab and small interfering RNA, or siRNA, therapies such as inclisiran. 

PCSK9 inhibitor mechanism of action

[2:18]
PCSK9 inhibitors bind to PCSK9 in the blood, preventing it from binding to LDL receptors. This does not stop the internalization of the LDL receptor and LDL particle. Inside the liver cell, LDL and cholesterol are processed as normal, but in the absence of PCSK9, the LDL receptors avoid degradation. Instead, they're packaged into an endosome and recycled back to the cell surface, where they can continue to remove LDL cholesterol from the bloodstream. SiRNA therapies, such as inclisiran, work at the genetic level by silencing the PCSK9 gene, reducing the production of the PCSK9 protein. We'll discuss this in greater detail later in the course.

Administering PCSK9 inhibitors

[3:09]
PCSK9 inhibitors include evolocumab, alirocumab, and inclisiran. Evolocumab and alirocumab are both given by subcutaneous injection available in a pen. Inclisiran, the newest PCSK9 inhibitor, is given by injection only twice a year. Evolocumab is also available in an on-body infuser device, where the medication is given slowly over several minutes for patients who have difficulty tolerating injections. 

When to use injectable cholesterol medication

[3:42]
These treatments are powerful, reducing LDL by 40 to 60% on their own. When combined with statins, LDL can be reduced by 50 to 60%. PCSK9 inhibitors were approved by the FDA in 2015 to be used in addition to dietary changes and maximally tolerated statins for patients with familial hypercholesterolemia or clinical CVD. They can also be considered for high-risk patients whose LDL remains elevated after other treatments, but these drugs are quite expensive.

PCSK9 inhibitor side effects: what to expect

[4:17]
Side effects are rare and include injection site reactions like erythema, pain or bruising for two to three days after each injection. Flu-like symptoms such as runny nose and back pain are extremely rare, and have only been seen with monoclonal antibodies such as evolocumab and alirocumab. PCSK9 inhibitors are safe and effective for lowering LDL cholesterol, but they can be expensive.

Prescribing injectable cholesterol medication: barriers and challenges

Cost and insurance approval challenges

[4:46]
In the US, insurance coverage often depends on a detailed review and approval can be challenging. Reimbursement policies vary by country, so these barriers might not apply everywhere. Prescribers may have to balance the clinical benefits of PCSK9 inhibitors against economic factors, often having to have difficult conversations with patients about the potential financial implications.
Navigating the insurance approval process can be a hurdle, and prior authorization is often needed, which requires the prescribing physician to justify the use of these expensive medications by demonstrating their necessity over other less costly options. This often includes detailed documentation of the patient's medical history and previous treatments, including evidence of statin intolerance or contraindications. Insurers may also need proof that the patient has a familial history of high cholesterol or has experienced previous cardiovascular events. The stringent approval process can increase prescriber workload and delay the start of treatment, posing a challenge for both patients and healthcare providers. 

Monitoring after starting PCSK9 inhibitors

[5:59]
Monitoring is also challenging and involves regular lipid profiling, adherence checks, and assessments for risk of cardiovascular events. It demands a collaborative effort between patients and healthcare teams, underscoring the importance for patient education and engagement.

Dosing schedule and patient adherence 

[6:18]
The infrequent dosing schedule of PCSK9 inhibitors, typically once or twice per month, depending on the specific medication, is a double-edged sword. On the one hand, it offers a convenient alternative to daily medication regimens, potentially improving patient adherence and quality of life. On the other hand, this schedule can present challenges in ensuring long-term follow-up and sustained adherence.
For example, patients with decreasing cognitive function may have difficulty remembering their dosing schedules, particularly if they do not have a regular routine or caregiver support to assist with medication management. The requirement for injections, whether done at home or in a clinical setting, adds another layer of complexity for these individuals. Incisiran, however, is administered by a general physician every six months, which improves compliance and adherence.

Long-term safety of PCSK9 inhibitors

[7:17]
Lastly, PCSK9 inhibitors have been shown to significantly lower LDL cholesterol levels and are generally well tolerated in the short and long term. Long-term follow-up studies have demonstrated that these therapies are not only effective, but also safe, with consistent results over time.