Beyond Statins: PCSK9 Inhibitors and the Future of Cholesterol Management

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Cholesterol is often misunderstood. While it is frequently linked to heart disease, it is actually a vital substance in the body, essential for building cell membranes, producing hormones like oestrogen and testosterone, supporting vitamin D synthesis, and helping with fat digestion through bile acids. The issue is not cholesterol itself, but how it behaves in susceptible individuals. In some people, elevated LDL (low density lipoprotein) cholesterol can contribute to the build-up of plaque in the arteries, a process known as atherosclerosis. But not everyone is equally at risk. Genetics, lifestyle, inflammation, and other health conditions all shape an individual’s likelihood of developing cardiovascular disease.

That is why decisions about cholesterol lowering treatment should always be tailored. Managing cholesterol is just one part of protecting your heart. Blood pressure, blood sugar, smoking, physical activity, and family history all play a role, and they often overlap. In this article, we focus on a newer group of cholesterol lowering medicines called PCSK9 inhibitors, including Repatha (evolocumab) and Leqvio (inclisiran). These injectable therapies are usually considered when LDL levels remain high despite the best efforts with diet, lifestyle and medication like statins, and ezetimibe. We will explore how they work, who might benefit, and how they fit into a broader strategy for long-term heart health.

When it comes to cholesterol, one size does not fit all. It is not just about the number, it is about how cholesterol interacts with your individual risk profile.

Why Lowering Cholesterol Matters

Cholesterol management is not just about numbers. It is about reducing the build-up of plaque inside the arteries, a process that can lead to heart attacks, strokes, or the need for stents and bypass surgery. Lowering LDL cholesterol is most effective when done in combination with:

• Controlling blood pressure
• Managing diabetes and insulin resistance
• Stopping smoking
• Encouraging movement, sleep, and healthy eating

For some individuals, especially those with established coronary disease or a strong genetic predisposition, lifestyle measures alone may not be enough to manage cholesterol levels. In these cases, medications such as statins, ezetimibe, and PCSK9 inhibitors can be important tools in reducing cardiovascular risk. When I speak with patients, I always aim to minimise the need for medication where possible, particularly in people who are otherwise healthy. That said, I am mindful that even well tolerated treatments can sometimes cause side effects that affect a person’s quality of life. This is why the decision to start cholesterol lowering therapy should always be considered in the broader context , taking into account the individual’s overall risk, any relevant test results such as stress testing, heart scans, or calcium scores, and whether they have a history of an established cardiovascular event e.g. heart attack, stent, heart surgery or stroke.

 

Understanding PCSK9

PCSK9 is a protein produced by the liver that affects how well your body clears LDL cholesterol from the blood. It targets LDL receptors, which are the parts of liver cells that remove LDL, and leads to their breakdown.

When there is too much PCSK9, fewer LDL receptors remain, and cholesterol builds up in the bloodstream.

PCSK9 inhibitors block the action of PCSK9, helping the liver clear more LDL from the blood and reducing overall levels.

 

Meet the Medications: Repatha and Leqvio

Repatha (evolocumab)

Repatha is part of a newer class of cholesterol lowering medications known as PCSK9 inhibitors. It is a laboratory made antibody that works by blocking a protein called PCSK9, which normally reduces the liver’s ability to remove LDL cholesterol from the blood. By preventing this interference, Repatha helps the body clear more LDL cholesterol, often achieving substantial reductions.

It is given as a simple injection under the skin, usually once every two weeks. Most people administer it themselves at home using a pen-like device, with minimal training. In clinical practice, it is generally well tolerated. Side effects are uncommon, but may include mild flu-like symptoms or injection site reactions in some individuals.

 

Leqvio (inclisiran)

Leqvio takes a different scientific approach. Instead of blocking the PCSK9 protein directly, it uses small interfering RNA (siRNA) technology to reduce the body’s production of PCSK9 at its source within liver cells. This genetic-level action lowers LDL cholesterol in a sustained way.

It is administered by injection, but less frequently than Repatha, one dose at the start, another at three months, and then every six months thereafter. This long lasting effect makes it an appealing option for those who prefer not to take medication regularly. Like Repatha, Leqvio is generally well tolerated, with a low rate of side effects. Some people may experience minor injection site discomfort.

 

When Are PCSK9 Inhibitors Considered?

These medications are not first-line treatments. They are typically used in people who remain at higher risk of cardiovascular events despite the following:

• Use of a maximally tolerated statin
• Addition of ezetimibe

PCSK9 inhibitors may also be useful in individuals with elevated lipoprotein(a), or Lp(a), where studies show these therapies may reduce Lp(a) by 20 to 30 percent. This is particularly relevant because no approved treatments currently target Lp(a) specifically.

For people with raised Lp(a), a PCSK9 inhibitor may offer added benefit, even if Lp(a) is not the primary treatment goal.

Efficacy: What the Studies Tell Us

 

Repatha: What the research shows

In a large study known as the FOURIER trial, people who were already taking statins added Repatha to their treatment. The results were encouraging:

• LDL cholesterol levels dropped by about 60 percent
• There was a lower chance of having a heart attack or stroke
• Fewer people needed urgent procedures to open up blocked arteries

This showed that Repatha can offer additional protection for people at high risk, beyond what statins alone can provide.

 

Leqvio: Long-lasting cholesterol control

Leqvio was studied in a group of trials called the ORION programme. These studies found that:

• LDL cholesterol levels were reduced by around 50 percent
• The effect was consistent and long lasting with just two injections a year after the initial doses

This makes Leqvio a convenient option for people who prefer not to take medication frequently but still need strong cholesterol lowering.

 

What About Statins?

Opinions about statins can vary. Some people are concerned about potential side effects or feel uncertain about taking them long term. The decision to use a statin should always be based on an individual’s overall cardiovascular risk. For those who have already experienced a heart attack, stroke, or other vascular event, statins remain a cornerstone of treatment. They help stabilise plaques, reduce inflammation, and lower the chance of future events. PCSK9 inhibitors can be added when additional cholesterol lowering is needed.

Ezetimibe is another important option, particularly for those who cannot tolerate higher doses of statins. It is generally well tolerated and can reduce LDL cholesterol by up to 25 percent. In my practice, I often find ezetimibe complements statin therapy well. I believe it may play a growing role in future treatment plans, potentially as part of a first line combination strategy for people at high risk. Ongoing clinical trials will help clarify this approach.

 

Side Effects and Safety of PCSK9 Inhibitors

Both Repatha and Leqvio are generally well tolerated, especially when compared to some older cholesterol lowering medications. They are not commonly associated with muscle aches or liver problems, two concerns that can arise with statins in some people. Most individuals are able to use these therapies without any significant side effects.

 

Repatha (evolocumab)

Repatha is given as an injection every two weeks (or monthly, depending on the dosing plan). It is usually well tolerated, but in some cases people may experience:

• Mild reactions at the injection site — such as redness, itching, or swelling
• Flu-like symptoms — including tiredness, chills, or low-grade fever
• Joint or back pain — this is less common and tends to be mild when it occurs

 

Leqvio (inclisiran)

Leqvio is given just twice a year after the initial loading doses, which many people find convenient. It also tends to be well tolerated. Possible side effects include:

• Mild discomfort or swelling at the injection site
• Occasional flu-like symptoms — such as fatigue or muscle aches, usually short lived

Most people who use either treatment report a positive experience, particularly when they understand how these therapies fit into their overall heart health strategy.

 

Most side effects are mild and short-lived. Many people find these treatments easy to continue long term, especially when balanced against their benefits.

 

A Holistic Approach to Heart Health

Cholesterol lowering therapy is just one part of the bigger picture. While it plays an important role, we know that heart health is influenced by many factors, often working together. In my own practice, I regularly talk with patients not only about their cholesterol levels, but also about what else might be contributing to their overall risk.
Taking a more holistic view means looking beyond lab results and thinking about how we live day to day. For the best protection against heart disease, it is important to also focus on:

• Blood pressure: Even slightly elevated readings over time can quietly increase cardiovascular risk. Monitoring and managing blood pressure is essential.
• Blood sugar and insulin resistance: Whether or not you have diabetes, keeping blood sugar in a healthy range helps protect your arteries.
• Smoking: One of the most powerful risk factors we can change. Stopping smoking, or never starting, can significantly reduce the chance of future heart events.
• Weight and physical activity: Staying active and maintaining a healthy weight can improve cholesterol, blood pressure, and overall wellbeing. Even small changes can make a difference.
• Stress and sleep: Often overlooked, but deeply important. Poor sleep and ongoing stress can affect heart rhythms, blood pressure, and daily decision making.

 

When we take a step back and look at the whole picture, not just one number, we can find more meaningful and lasting ways to protect the heart. It is about supporting the whole person, not just managing cholesterol.

 

Whether you are just beginning your heart health journey or reviewing your current plan, I always encourage patients to think about which areas feel manageable right now. Small steps taken consistently can lead to big improvements over time.

 

Taking a step back to consider the whole person, not just cholesterol, leads to more meaningful and lasting heart health.

Conclusion

PCSK9 inhibitors such as Repatha and Leqvio offer another option for people who need additional support in lowering their LDL cholesterol, particularly when lifestyle changes, statins, and ezetimibe have not been enough. They may play an important role for those with existing heart disease or inherited cholesterol conditions, where bringing levels down further can help reduce the risk of future events.
As with any treatment, the decision to use a PCSK9 inhibitor should be guided by individual risk and discussed carefully with your healthcare team. My hope is that understanding how these therapies work, and where they fit in, helps you feel more informed and confident when navigating your options. The path to better heart health is rarely one size fits all, but having the right tools and knowing when to use them can make a real difference.