Cholesterol has a reputation problem. For decades it has been labelled as something to fear, a villain lurking in our bloodstream waiting to cause harm. But the reality is more nuanced, and I think it is important to be clear about this with patients from the outset.

Cholesterol is not inherently bad. It is a vital substance, essential for building every cell membrane in the body, producing hormones like oestrogen and testosterone, supporting vitamin D synthesis, and helping with fat digestion through bile acids. In truth, all cholesterol serves a purpose. The issue is not cholesterol itself, but the balance between different types, and crucially, how that balance interacts with your individual risk profile.

I often tell my patients: rather than thinking of HDL as “good cholesterol” and LDL as “bad cholesterol,” it is more helpful to think of them as different vehicles carrying cholesterol around the body, and that problems arise not from the cholesterol itself, but from what happens when too much of it accumulates in the wrong places, particularly in the walls of the arteries.

Why LDL Levels, and Inflammation, Matter

Elevated LDL cholesterol can contribute to the build-up of plaque inside the arteries, a process known as atherosclerosis. But the number on a blood test tells only part of the story. Plaque build-up is not simply a passive accumulation of cholesterol, it is an active, inflammatory process.

Within arterial plaques, inflammatory cells gather and accumulate. These cells are not passive bystanders, they are active participants in a process that can destabilise and ultimately rupture plaque. It is this rupture that triggers the sudden formation of a blood clot, and it is that clot which causes a heart attack or stroke. Lowering LDL is therefore not just about reducing a number, it actively reduces the inflammatory environment within the artery wall, making plaques more stable and less likely to cause harm.

This is one of the reasons why the benefits of cholesterol-lowering therapy extend beyond what the LDL reduction alone would predict. The anti-inflammatory effect is a critical part of the story.

Lowering LDL is not just about a number, it actively reduces inflammation within the artery wall, making plaques more stable and less likely to rupture. It is the rupture, not the plaque itself, that causes a heart attack.

The Role of Lp(a), A Genetic Risk Factor Worth Knowing About

In recent years there has been growing appreciation of another important marker, lipoprotein(a) commonly written as Lp(a). Unlike LDL, which is significantly influenced by diet and lifestyle, Lp(a) is largely determined by genetics. You are born with a certain Lp(a) level, and it stays relatively constant throughout life.

Elevated Lp(a) is now recognised as an independent risk factor for cardiovascular disease, meaning it adds risk on top of LDL, blood pressure, and other conventional factors. It is particularly relevant in people who develop heart disease at a young age, or who have a strong family history of cardiovascular events.

One of the clinically important aspects of Lp(a) is its genetic nature. If a patient has significantly elevated Lp(a), it raises the question of whether their siblings or children should also be tested, as they may carry the same inherited vulnerability. This kind of family screening can be genuinely life-changing, identifying people at risk before they ever have an event.

PCSK9 inhibitors are one of the few currently available therapies that can meaningfully reduce Lp(a), by around 20–30%. While Lp(a) lowering is not always the primary goal of treatment, it represents a meaningful added benefit for patients who have both elevated LDL and elevated Lp(a).

Understanding PCSK9, What Is It?

PCSK9 is a protein produced by the liver. Its role is to break down LDL receptors, the structures on liver cells that remove LDL cholesterol from the bloodstream. When PCSK9 is overactive, fewer LDL receptors survive, and LDL accumulates in the blood.

PCSK9 inhibitors block this protein, allowing more LDL receptors to remain active. The liver is then able to clear more LDL from the bloodstream, often achieving dramatic reductions in cholesterol levels, alongside the anti-inflammatory benefits described above.

Repatha vs Leqvio, How Do They Compare?

There are currently two main PCSK9 inhibitors widely available. They both lower LDL effectively but work through different mechanisms and have different dosing schedules.

What the Evidence Shows

Both medicines are backed by substantial clinical trial data.

Repatha was studied in the landmark FOURIER trial, in which patients already taking statins added Repatha to their treatment. LDL cholesterol dropped by approximately 60%, and there was a meaningful reduction in the risk of heart attack, stroke, and the need for urgent procedures to open blocked arteries.

Leqvio was studied in the ORION programme, which found consistent LDL reductions of around 50% maintained with just two injections per year after the initial loading doses, making it a particularly convenient option for patients who prefer a less frequent treatment schedule.

When Are PCSK9 Inhibitors Considered?

These medications are not first-line treatments. They are typically considered when other measures have not achieved adequate cholesterol control or when cardiovascular risk remains high.

As always, the decision to start any cholesterol-lowering therapy should be made in the context of your full cardiovascular risk profile, taking into account test results, family history, and your personal circumstances. This is a conversation worth having carefully with your doctor or cardiologist.

What About Statins and Ezetimibe?

Statins remain the cornerstone of cholesterol management for people with established heart disease or high cardiovascular risk. Beyond lowering LDL, statins have important anti-inflammatory and plaque-stabilising effects, reducing the likelihood that vulnerable plaques will rupture and cause an event. PCSK9 inhibitors build on these benefits when further LDL reduction is needed.

Ezetimibe is another valuable option, particularly for those who cannot tolerate higher doses of statins. It reduces LDL by up to 25% and is generally very well tolerated. In my practice I find ezetimibe complements statin therapy well, and it is often a sensible step before considering a PCSK9 inhibitor.

Side Effects and Safety

One of the reassuring aspects of PCSK9 inhibitors is their tolerability. Unlike statins in some patients, they are not commonly associated with muscle aches or liver problems. Most people use these therapies without significant side effects.

The most commonly reported issues are mild injection site reactions, redness, itching, or brief swelling, which typically resolve quickly. Some people notice occasional flu-like symptoms or fatigue for a day or two after an injection. These are generally short-lived and rarely lead to stopping treatment.

The Bigger Picture

Cholesterol-lowering therapy, however effective, is just one part of protecting your heart. Blood pressure control, blood sugar management, stopping smoking, staying active, maintaining a healthy weight, getting quality sleep, and managing stress all contribute meaningfully to long-term cardiovascular health.

When we look beyond a single number and consider the whole person, their genetics, their lifestyle, their family history, and their inflammatory risk, we find more lasting and meaningful ways to reduce the chance of a future event. That is the approach I take with every patient, and it is the spirit behind everything we write here at Heart Matters.

Conclusion

PCSK9 inhibitors represent a genuine advance in cholesterol management, offering powerful LDL reduction, meaningful Lp(a) lowering, and important anti-inflammatory benefits for people who need additional support beyond statins and ezetimibe.

For those with established heart disease, familial hypercholesterolaemia, elevated Lp(a), or persistently high LDL despite other treatments, they can make a real difference to long-term cardiovascular risk. The decision to use them should always be guided by your individual risk profile and discussed carefully with your healthcare team.

And if your doctor mentions Lp(a), it is worth asking whether your close family members should be tested too. That conversation could matter more than you know.