First up, what is PCSK9 and why would you want to inhibit it? The short answer is that PCSK9 is a protein that helps regulate cholesterol levels. The more you have, the more likely you are to have high LDL-cholesterol. So, if you have high cholesterol, you’d want to take a PCSK9 inhibitor, right? Not so fast.
In this article, I look at PCSK9, what the gene does and why drugs that inhibit PCSK9, while they are backed by promising data, might not be a good fit for everyone with high cholesterol.
What is PCSK9?
PCSK9 is a protein discovered in 2001 that is encoded, unsurprisingly, by the PCSK9 gene. This protein facilitates the breakdown of LDL receptors in cells and prevents them from returning to the surface of cells to scoop up more LDL-cholesterol. Need a crash course on cholesterol clearance? We’ve got you covered here.
So, PCSK9 inhibitors prevent PCSK9 protein from grabbing onto the LDL receptors. This means more of the receptors are able to return to the surface of your cells to scoop up LDL-cholesterol.
PCSK9 inhibitors also do something else to keep LDL-C in check – they decrease levels of apolipoprotein B, non-high-density lipoprotein cholesterol, and lipoprotein(a). 1 This has the effect of increasing the particle size of very low-density lipoprotein (VLDL), making it less atherogenic, i.e. less bad for the heart and arteries.
So, let’s assume you have high LDL-cholesterol and are looking for a way to get your cholesterol back into a healthy range. Should you take PCSK9 inhibitors? Quite possibly, but not necessarily.
If you have a genetic variant of the PCSK9 gene that means you don’t make much or any of this protein, you are almost guaranteed to have low LDL-cholesterol. However, the reverse is not always true; not everyone with high LDL-cholesterol can blame an overabundance of PCSK9.
Many factors influence your LDL-C levels. PCSK9 predominantly affects the clearance of LDL-C, but not everyone with high LDL-C has a clearance issue. In fact, problems with cholesterol clearance are only one of the three core ways LDL-C reaches dangerously high levels. The other two ways – synthesis and absorption – are not the primary target of PCSK9 inhibitors. Here, more pertinent factors might include:
- Saturated fat intake
- Lack of exercise
- Liver disease
- Genetic variants of LDLR, APOB, or other genes involved in cholesterol synthesis and metabolism.
So, who should take a PCSK9 inhibitor?
The US Food and Drug Administration approved two PCSK9 inhibitors, alirocumab (Praluent) and evolocumab (Repatha), in 2015. However, PCSK9 inhibitors are currently only approved for people with familial hypercholesterolemia (FH). This condition is caused by multiple factors and is characterized by very high cholesterol levels and an increased risk of early heart disease and stroke.
At first, the FDA only approved these drugs for individuals who were heterozygous for FH or those with atherosclerotic cardiovascular disease who had an insufficient response to other interventions. Subsequently, data from the TESLA trial led to Evolocumab’s approval being extended to people homozygous for FH, based on an 18-44% reduction in LDL-cholesterol over three months in those with at least 2% functioning LDL receptors. 2
Indeed, the 2018 Cholesterol Guidelines from the American College of Cardiology suggest considering the use of PCSK9 inhibitors for some people who haven’t been able to decrease LDL-C below 70 mg/dL despite using the highest dose of statin they can tolerate in addition to ezetimibe.
But, if a drug can help lower LDL-cholesterol that much in some people, why not approve it for everyone with high LDL-cholesterol?
One answer is that for PCSK9 inhibitors to work, they need something to inhibit. If a person has no functioning LDL receptors to begin with, there’s not a lot of point giving them a drug that aims to help keep receptors in circulation. That said, even in these cases, a PCSK9 inhibitor can still have benefits for controlling apolipoprotein B levels.
In those with certain mutation of the LDLR gene, or even some mutations in the APOB gene, PCSK9 isn’t the issue, or might not be the only issue anyway. Instead, it is the LDL receptor itself that is dysfunctional, or the way that low-density lipoprotein tries to bind to the receptor.
When to take a PCSK9 inhibitor
Chances are that if you have high LDL-cholesterol, your doctor will prescribe you a statin and give you some basic dietary and lifestyle advice. For most people, statins are extremely helpful and can dramatically reduce the risk of major adverse cardiovascular events. What if you’ve taken the statins, though, and your cholesterol levels don’t budge or don’t budge much?
If statins con’t seem to work for you or you have an extreme adverse reaction to them, your doctor may consider taking a new approach. This might mean adding in a drug such as ezetimibe. The primary action of ezetimibe is to reduce cholesterol absorption in the intestine. This is great for hyper-absorbers. Ezetimibe can also lower apolipoprotein B levels and may help guard against absorption of plant sterols, so it’s certainly worth a shot.
What if all of these measures, plus dietary and lifestyle modifications, haven’t improved your lipid profile? This is where you might start to consider a PCSK9 inhibitor.
What the research says about PCSK9 inhibitors
Research shows that PCSK9 inhibitors reduce LDL cholesterol considerably better than ezetimibe. 3 These drugs can help 70% of individuals at high risk of hypercholesterolemia to get their LDL-C below 70 mg/dL.4 This is the magical number most doctors aim for, but it’s still not low enough for most people to normalize their risk of cardiovascular disease.
PCSK9 drugs are very effective at lowering LDL-C, and almost certainly help prevent heart attacks and strokes in some individuals. Multiple phase II and III studies have found that these drugs reduce LDL-C levels by up to 60%. Two randomized controlled clinical trials also demonstrated that both drugs reduce atherosclerotic cardiovascular disease (ASCVD) events when used in combination with statins compared to statin alone. 5
In a 2018 review of Phase II, phase III, pooled, post hoc, and cardiovascular (CV) trials, researchers found that in all trials, alirocumab and evolocumab led to significant reductions in LDL-C. Two trials found a decrease in major adverse cardiovascular events (MACE) with PCSK9 inhibitor use, with one showing a decrease in all-cause mortality with alirocumab use.6
Put simply, PCSK9 inhibitors are the bomb when it comes to reducing LDL-cholesterol. So, why wouldn’t you want to take one?
Downside of PCSK9 inhibitors
Unfortunately, PCSK9 inhibitors are a costly way to reduce LDL-C and few insurance plans will cover that cost. The authors of the 2018 analysis mentioned above concluded that PCSK9 inhibitors are only cost effective for folks with the highest risk of CVD events and LDL-C levels that remain high even with statin therapy. The cost of PCSK9 inhibitors would need to decrease significant for their use to be considered more widely. 6
The other downside, for some, is that PCSK9 inhibitors have to be injected. They’re not oral medications.
Potential side effects of PCSK9 inhibitors
PCSK9 inhibitors don’t seem to be associated with any more adverse effects than placebo. Those reported most commonly in trials include upper respiratory tract infections, nasopharyngitis, influenza and reactions at the site of injections. Evolocumab has also been associated with back pain.
But, because these drugs have only been approved for the last five years, we don’t yet understand the potential long-term effects of Praluent and Repatha. Studies have also noted that PCSK9 inhibitors may, in theory, increase susceptibility to hepatitis C viral infection. 7 This is because the PCSK9 protein reduces the expression of CD81, a co-receptor for Hepatitis C virus infection. In essence, PCSK9 may protect against hepatitis C infection, meaning that PCSK9 inhibitors could increase the risk of infection. This has not been seen in studies using lab mice, however.
One other potential concern is the effect of PCSK9 inhibitors on blood glucose regulation. Some research found that inhibiting PCSK9 in the pancreatic islet beta cells of mice led to hypoinsulinemia, hyperglycemia and glucose-intolerance. The drugs were also associated with malformations and faster death of the islet cells as well as increased inflammation. Clinical trials in humans haven’t observed these effects, however. 8
All in all, PCSK9 inhibitors show a lot of promise and, once the cost goes down, may rapidly become a first-line treatment for high LDL-C. Convincing your insurer to cover that cost, though, may be tough, which puts them out of reach for most folks. In the meantime, then, is there any way to hack PCSK9 yourself?
Alternatives to PCSK9 inhibitors
PCSK9 is a fairly fresh face in the field of lipid research, but a handful of trials have noted that fasting reduces levels of the protein, as do omega-3 fatty acids. Conversely, fructose increases the expression of PCSK9.9
One recent study found that an alginate oligosaccharide (AOS) reduced levels of PCSK9. This AOS also increased the expression of LDLR and the uptake of LDL-C in liver cells. 10
Another study looked at a polypeptide from soy, called Lunasin. This polypeptide decreased expression of PCSK9, which may, in part, explain why dietary soy is associated with reductions in cholesterol.11
Now, none of these alternatives are likely to be anywhere near as effective as a PCSK9 inhibitor. But they could be worth a shot in conjunction with a statin and ezetimibe.
Mutations in PCSK9, LDLR, and APOB cause the autosomal dominant disorder, familial hypercholesterolemia (FH). Some folks with a mutation in PCSK9 have pretty normal LDL-C levels. Other have very low LDL-C levels. And some have very high levels. This depends on the type of PCSK9 mutation, as well as environmental effects and modifying genes.
You and your health care practitioner will need to weigh all the factors and decide whether a PCSK9 inhibitor is right for you. If your genome shows a problem variant of PCSK9, these drugs might be worth a shot. With the current guidelines, however, good luck convincing your insurance company to pay for these drugs.
In the meantime, your best bet for reducing LDL-C is likely to be sticking with a statin and ezetimibe. These primarily help lower cholesterol by targeting cholesterol synthesis (statins) and cholesterol absorption (ezetimibe). Coupled with recommended lifestyle and dietary modifications, these can help most folks get their LDL-C under control. But, just in case, you might also want to try a few of the PCSK9 inhibition hacks mentioned above.