An Expert's Guide to Managing Familial Hypercholesterolemia



April 21, 2021

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This transcript has been edited for clarity.

Hi. I'm Seth Baum, a preventive cardiologist and clinical lipidologist in Boca Raton, Florida. I'm also the past president of the American Society for Preventive Cardiology and on the faculty at the Florida Atlantic University Charles E. Schmidt College of Medicine.

I'm happy to be here today to talk about familial hypercholesterolemia (FH), and specifically homozygous familial hypercholesterolemia (HoFH) and heterozygous familial hypercholesterolemia (HeFH). However, before getting into that, I want to first recommend a wonderful website that can help clinicians and patients alike understand FH, work through insurance issues that can sometimes occur with certain medications, and access collateral materials and patient support groups: TheFHFoundation org. I highly recommend you go there and avail yourself of their excellent resources.

HeFH: A Common Disorder That Remains Overlooked

One of the most important things to know about HeFH is that it's actually quite common, occurring in approximately 1 in every 200-250 people. This means that within nearly every single practice in the United States there are patients with HeFH. Just several years ago, it was estimated that 99% of patients with HeFH were undiagnosed. We've done better since then, but it's likely that 90% these patients still need to be diagnosed. They're hidden within our practices.

FH is a genetic disorder. It's an autosomal dominant or co-dominant disorder typically affecting the low-density lipoprotein (LDL) receptor and rendering it defective. FH can be caused by other genetic mutations occurring in the apolipoprotein B (APOB) or PCSK9 genes, but the dominant cause resides in the LDL receptor.

Because it's a genetic disorder, that means that it's passed along to children. Therefore, if we look within our practices and identify patients with FH, we can then do cascade screening and identify many others with FH. Investigators in the Netherlands have used this approach very effectively, reporting that every proband (first patient) identified with HeFH led to an additional seven or eight patients identified.

The relatively high prevalence of HeFH increases the need to identify patients because this is a very damaging disease, which leads to elevated LDL cholesterol and particles. By now, I think we all know that the LDL hypothesis is dead. LDL definitely causes vascular disease. Patients with elevated LDL cholesterol have an increased risk for atherosclerotic cardiovascular disease events, which is very much true in patients with HeFH. In the most severe cases, the risk for such events is greater than 20 times that of the general population.

HeFH can lead to rather extreme outcomes because LDL is elevated on a genetic basis, not just on an environmental basis. When children with this condition are in utero, their LDLs are actually already very high and remain so throughout life unless the LDL is treated.

Diagnosing and Treating HeFH

Although HeFH is a genetic disorder, we diagnose it clinically. Genetics can come into play and be very valuable at times. This is especially true when we perform cascade screening to identify other family members with this condition, and when we detect specific mutations that can confer a higher risk profile. But genetics does not trump the clinical diagnosis. In fact, it's the other way around: Phenotype always trumps genotype.

After diagnosing HeFH through phenotypic identification, we then do a genetic test. If the genetic test identifies no mutations, that does not mean the patient doesn't have FH. It simply means that the patient's mutations have not yet been identified and we still consider them to have the condition.

There are three systems in place to can help us diagnose FH: the Dutch Lipid Clinic Network, Simon Broome Criteria, and the US Make Early Diagnosis to Prevent Early Death (MED-PED). But an even simpler way to start the process is to first assess patients' LDL levels. The LDL threshold levels we use for identifying HeFH are >190 mg/dL for untreated adults, ≥ 160 mg/dL for people between the ages of approximately 10 and 20 years, and ≥ 130 mg/dL for younger children. If one were to have an LDL in that range, in addition to having a family history of high cholesterol and especially a family history of premature heart disease, we can then make the diagnosis on phenotypic grounds.

After we make that diagnosis, we need to — of course — treat these patients. We sometimes lack a sense of urgency when treating patients for cholesterol issues. However, for patients with FH, there is a need for tremendous urgency because "time is plaque." The longer the LDL is up, the greater the likelihood plaque will develop and that cardiovascular events will occur. So, we need to treat early and aggressively.

Treatment begins with standard lipid-lowering therapy: statins, ezetimibe, and PCSK9 inhibitors. Whether or not an individual has established arteriosclerotic cardiovascular disease will determine the goal of lipid-lowering. In our sickest patients, the European guidelines stipulate getting their LDL < 40 mg/dL. Here in the United States, we typically try to get patients who are a little less sick and under 55 years of age to < 70 mg/dL.

In addition, there are also physical findings that we can use to identify patients with FH, such as tendon xanthoma, with Achilles tendon xanthomas being the most commonly described. When performing a physical exam on patients, it's important that clinicians not only feel their pedal pulses but also feel the Achilles tendon. Get a sense of how thin the Achilles tendon is normally, so that you'll recognize it when it's thicker, as in the case of xanthomas. It's not always going to be a giant xanthoma that's irregular and can instead just be a generalized thickening of the Achilles tendon. Xanthomas can also occur on the extensor tendons in the hands and on the elbows. We may also see xanthelasma or corneal arcus in patients before the age of 45, which is pretty much pathognomonic for FH.

HoFH: Similar Diagnosis, but a More Complicated Genetic Picture

The diagnosis of HoFH, as with HeFH, is really done on clinical grounds. Again, phenotype trumps genotype. We again use an LDL diagnosis in the proband case, looking for levels > 300 mg/dL in those on lipid-lowering therapy or > 400 mg/dL in those not on lipid-lowering therapy, as well as family history and personal history of arteriosclerotic cardiovascular disease.

When considering the family history, we're looking at both sides of the family for context. Remember, HoFH means Mom and Dad have each contributed a mutation to make this occur in the offspring. So, on each side of the family, there has to be elevated cholesterol and/or premature heart disease.

Of course, an LDL > 400 mg/dL is pretty high. It turns out that LDL can actually vary quite significantly in this population and could be even < 200 mg/dL in the untreated state. Although that's important to know, the reality is that the risk from HoFH is an LDL risk. It's obviously less essential to consider HoFH in somebody with an LDL of 200 mg/dL than in somebody with an LDL of 500 mg/dL. You want to treat that LDL and get it down as low as possible.

Mutations in APOB and PCSK9 can cause HoFH, but again, it's much more common for mutations to the LDL receptor to be the main contributor. Yet the genetic diagnosis of HoFH can be a little confusing.

There are three different types of patients with HoFH from a genetic standpoint. The first is someone who has simple HoFH, meaning they have a mutation in the same gene with each parent contributing the same mutation in the same gene, typically in the LDL receptor.

Another classification is called "compound heterozygous." This is confusing, given that you're using the term "heterozygous" to diagnose a homozygote, but that's just the way our nomenclature works. A compound heterozygote would be somebody who's got mutations from their mother and father in the same gene, but different mutations. For example, the patient may have mutations in the LDL receptor, but it's one mutation from their mother and a different one from their father.

Finally, there is a double heterozygote, which refers to somebody with different genes being affected — one from their mother and one from their father— and different mutations. That person can have an LDL receptor mutation from their mother and a PCSK9 mutation from their father, for example.

Another thing you need to know about the genetics of HoFH is that the degree to which the LDL receptor is affected also affects the degree to which LDL will be elevated in the patient. There are two separate categories for this: null and defective mutations. A null mutation causes < 2% normal activity/functionality in the LDL receptor, whereas a defective mutation causes between 2% and 25% of normal activity/functionality. A null-null mutation means both the mother and father have contributed a null mutation. Patients with null-null mutations are our sickest and, in a very significant way, our toughest to treat.

Early Risks Necessitate an Aggressive Treatment Approach

It's important to understand that because the LDL is so very high in people with HoFH, they can experience cardiovascular events when they're under the age of 10 and even cardiovascular death resulting from a myocardial infarction by the age of 5.

We therefore have to identify these patients when they're very, very young and differentiate HeFH from HoFH, because the treatment is much more aggressive for the latter condition. Treatment is also very aggressive for HeFH, but it has to be even more so for HoFH. There are also treatments available for HoFH that are not indicated in HeFH, which is an important distinction.

Let's say we've identified a child with HoFH. What do we do then? By the age of 5, that child should be on a statin, and potentially a statin and ezetimibe and even more. Certainly, lipoprotein apheresis would be an excellent therapy for a child with HoFH. And these treatment options hold true through adulthood: a statin, ezetimibe, PCSK9 inhibitor, apheresis.

If we need even more therapeutics, there are a couple of drugs that are available. Lomitapide is an oral microsomal triglyceride transfer protein inhibitor, which basically blocks the production of very low-density lipoprotein (VLDL) in the liver. It's an effective drug that, unfortunately, has issues of gastrointestinal tolerability and the potential for hepatic steatosis, which limits its use. The other drug is mipomersen, an antisense oligonucleotide to APOB, which is given by injection. That too carries some significant issues, particularly involving hepatic abnormalities resulting from steatosis.

Just recently, the US Food and Drug Administration announced that it had approved a new add-on treatment for HoFH in individuals 12 or older, the angiopoietin-like protein 3 (ANGPTL3) inhibitor evinacumab.

Understanding how this drug works requires a reminder of normal lipid physiology. VLDL is a large lipoprotein, consisting mostly of triglyceride with a little cholesterol. VLDL is secreted from the liver and travels around the body, making a number of different trips where it drops off triglycerides, adipose tissue, or skeletal muscle. The enzyme lipoprotein lipase is instrumental in hydrolyzing these triglycerides so that they can go to skeletal muscle and adipose tissue. VLDL shrinks down, becomes remnants known as "intermediate-density lipoproteins," and ultimately LDL. Intermediate-density lipoproteins can be taken up by the liver through remnant receptors and other canonical and noncanonical mechanisms. But ultimately what happens is that LDL receptors in the liver pick up LDL particles, metabolize them, and therefore keep our LDL down.

Under the circumstances of HoFH, where we have defective or null receptors, the LDL backs up because it can't go to the liver to be degraded. We still have all this other stuff going on with remnant receptors, but it's insufficient to lower our LDL. This leads to excessive levels of LDL in the blood.

It turns out that ANGPTL3 acts like a natural break on two enzymes: lipoprotein lipase and endothelial lipase. When this natural break is removed, we essentially "de-repress" endothelial lipase and lipoprotein lipase. Interestingly, and actually quite surprisingly, endothelial lipase is instrumental in altering the remnant particles in some manner that makes them much more readily metabolized by the liver. This occurs through some receptors that we understand and some that we do not understand or have not yet identified. What ends up happening is that those precursors for LDL are significantly decreased, thereby decreasing the amount of LDL in the blood, even in the absence of any LDL receptor activity.

In a key study of evinacumab in patients with HoFH, investigators found that LDL was reduced about 50%, which is remarkable given that this is a very high-risk, difficult-to-treat patient population. Even in patients who have null-null receptors, meaning no LDL receptor activity at all, there was a 50% reduction in LDL cholesterol in the blood. In contrast, when PCSK9 inhibitors are used in patients with null-null receptors, there is zero reduction in LDL. Even under the best-case scenario where receptors are defective-defective, there is well below a 50% reduction.

Therefore, evinacumab has become a very important treatment strategy in HoFH. It's administered intravenously every 4 weeks at 15 mg per kg. It is available now for appropriate patients with HoFH, of which there are probably around 1500 or so in the United States.

In conclusion, I recommend you take advantage of the tremendous resources at, pay a lot of attention to these patients, and understand that there are those with HeFH in your practice right now and you need to identify them early and treat them aggressively to avoid the complications of cardiovascular events.

Thank you very much.

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