Familial Hypercholesterolemia (Part 2): What Is the Optimal Treatment?

Eric Bruckert, MD, PhD; Boris Hansel, MD


June 11, 2015

Dr Bruckert: Well, the only alternative that's currently available is the resin cholestyramine. It's quite effective, given that up to about two or three sachets of Questran® lower the LDL cholesterol level by 20%. The drawback with this drug is that it's often poorly tolerated because it tastes bad, and it causes gastrointestinal problems. Because it's not well tolerated, we keep this treatment "in reserve" to some extent.

Dr Hansel: And it has to be taken several times a day, with the result that there's a risk for poor compliance.

There's also apheresis, which can be proposed in the severe forms. Currently, what are the indications for LDL apheresis, a type of plasmapheresis for removing cholesterol from the bloodstream?

Dr Bruckert: For those not familiar with this procedure, the principle of LDL apheresis is, as explained to our patients, to filter blood on columns that capture the LDL. There are two very well-accepted indications:

  1. As primary prevention, when the LDL cholesterol level is greater than 300 mg/dL in a patient receiving the maximum oral treatment; and

  2. As secondary prevention, when the LDL cholesterol level is greater than 200 mg/dL in a patient receiving the maximum treatment.

These two indications for LDL apheresis are absolutely indisputable.

Dr Hansel: When it comes to patients with familial hypercholesterolemia whose levels are high because they don't tolerate statins or ezetimibe, we're presently somewhat unequipped. But there are some drugs in the pipeline, such as proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors. You will recall that PCSK9 is a molecule that binds to LDL receptors and that blocks their breakdown. Therefore, if we inhibit PCSK9, we will lower the LDL cholesterol level.

We've heard a lot about those inhibitors at conferences. What's their current status? Is it really a new era for patients with hypercholesterolemia? And when can we hope to have access to these treatments?

Dr Bruckert: It's clearly a major advance, because their efficacy is well documented and well demonstrated. They reduce the LDL cholesterol level by at least 50%. Therefore, in terms of efficacy, there is no doubt.

From the standpoint of tolerance, it's a bit early to draw any definitive conclusions, because these drugs are in the developmental stage. However, so far, the only indication of tolerance issues is problems with cognitive function in a few patients, but these are extremely rare. Apart from that, these drugs are remarkably well tolerated.

From a practical standpoint, we simply have to keep in mind that they are injectables; they are therefore a subcutaneous treatment.

Dr Hansel: But one that's not administered daily.

Dr Bruckert: Every 15 days or every month. So, for now, their efficacy is there. The tolerance, on the basis of experience up to the present time, is there, too.

Of note, there are two recent, important publications in the New England Journal of Medicine reporting that the patients who were treated with these drugs experienced a very impressive cardiovascular risk reduction. The study populations were small, so we can't draw any definitive conclusions. However, this looks quite promising.[5,6]

Dr Hansel: Do we have any idea when they will arrive on the market in Europe?

Dr Bruckert: There's the marketing authorization and then there's coverage, so I don't think these drugs will be available for at least 2 years.

[Editor's note: On May 25, 2015, the European Medicines Agency (EMA) recommended authorizing the PCSK9 inhibitor evolocumab as treatment to lower high levels of cholesterol in people who are unable to control their cholesterol despite taking optimal doses of statins or who cannot take statins.[7] This week (June 9-10, 2015), the FDA advisors recommended alirocumab approval, citing value in FH, and an FDA panel recommended the PCSK9 inhibitor evolocumab for approval.]

Dr Hansel: Two or 3 years. Are there any other drugs presently being developed?

Dr Bruckert: There's another drug, lomitapide, for the extremely severe forms of hypercholesterolemia (the homozygous form). I recall it being for young children who have a cholesterol level of practically 1000 mg/dL and who develop cardiovascular disease before the age of 13 or 14 years. So, it's a very severe form. All of them are treated by apheresis and as early as possible, but lomitapide is potentially effective and might be useful in this particular, very severe form of hypercholesterolemia.

Dr Hansel: Does it, too, have side effects?

Dr Bruckert: Yes. It has some side effects, including hepatic side effects, but the benefit in terms of LDL cholesterol nonetheless justifies its use, or will justify its use once it's covered.

[Editor's note: Mipomersen, an antisense oligonucleotide that blocks apolipoprotein B, was approved by the US Food and Drug Administration in January 2013 to treat inherited cholesterol disorder. However the EMA refused its marketing in December 2012 owing to safety concerns.][8,9]

Which Treatment Should Be Administered to Children?

Dr Bruckert: The pediatric guidelines are very clear: Treatment is started at the age of 8-10 years, when the familial form has been clearly diagnosed, because one must not treat just any form of hypercholesterolemia in children. We individualize the dose. Often we start with pravastatin 10-20 mg, but actually, we can use any statin in children, when necessary.

Dr Hansel: When do you recommend turning to a lipid specialist (an endocrinologist, internist or other who specializes in lipid disorders)? In adults, would it be as soon as one has difficulty achieving the objectives with statins? Can we give that as an advice?

Dr Bruckert: Yes; I find this to be very good advice. Consulting a lipid specialist can be very useful:

  • For making a genetic diagnosis, if one has difficulty doing this at the local level;

  • For doing a noninvasive cardiovascular workup, especially in patients over the age of 40 years; and

  • When there is difficulty with the treatment.

Dr Hansel: Many thanks, Professor Bruckert.


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