Detection and Treatment of Severe FH Depends on LDL Levels, Not Genes, Says Expert Panel

A new review by an international panel of experts is refining the identification of patients with familial hypercholesterolemia (FH), specifically those with the most severe type of the lipid disorder, and outlines a treatment algorithm that includes high-intensity statin therapy and ezetimibe (Zetia, Merck/Schering-Plough) as the first line of therapy in these high-risk patients.

Given that atherosclerotic cardiovascular disease is directly related to chronic exposure of significantly elevated LDL cholesterol concentrations, the panel specifically defines FH based on LDL cholesterol levels rather than its genetic underpinnings.

“Although future personalized medicine might benefit from knowledge about genomic background, and detection of the pathogenic mutation can support family screening, identification of a causative gene variant is not essential for either diagnosis or treatment decisions, since these are guided more appropriately by LDL cholesterol concentration and not by genotype,” writes Raul Santos, MD (University of São Paulo Medical School Hospital, Brazil), the chair of the International Atherosclerosis Society (IAS) Severe FH Panel, and colleagues May 27, 2016 in the Lancet Diabetes and Endocrinology.

FH is classified into heterozygous and homozygous forms depending on the presence of one or two affected alleles in genes that encode the LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9). However, as the IAS panel argues, stratification of disease based on a genetic diagnosis is difficult because such categorizations—non-mutated, heterozygous, or homozygous—no longer adequately describe the risk considering the overlap in LDL concentrations.

For example, some patients with heterozygous FH can have LDL cholesterol levels typically characteristic of homozygous FH patients, which would be in the range of 400 to 500 mg/dL. The opposite also is true, in that some homozygous FH patients can have LDL concentrations significantly lower than expected based on their genetic makeup (in the range of 190 to 400 mg/dL).

Since elevated concentrations of LDL cholesterol are the main drivers of cardiovascular risk—and not the causative mutations—there is a need to define the severe phenotype of FH, one that includes high-risk patients regardless of whether they have molecularly defined heterozygous or homozygous FH, according to the IAS.

For Joshua Knowles, MD (Stanford University Medical Center, CA), the new review is an attempt to put a “fine point” on the classification of individuals with a very severe phenotype. Although not involved in the IAS consensus statement, Knowles, who is the chief medical officer of the US-based FH Foundation and was a committee member of the 2015 American Heart Association scientific statement on FH, told TCTMD in an email some patients with FH are being denied access to medications so the review helps identify those who might benefit the most from very expensive pharmacotherapy.

Like the IAS, the AHA statement on FH also allows physicians to diagnose FH without genetic testing, although a positive genetic test for LDLR, APOB, or PCSK9 are criteria than can also be used. 

How to Treat Severe FH: an Algorithm

Based on the IAS proposed criteria, severe FH is diagnosed if LDL cholesterol levels exceed 400 mg/dL. If the patient has one or two high-risk cardiovascular features, severe FH can be diagnosed if LDL cholesterol levels exceed 310 and 190 mg/dL, respectively. High-risk features include a family history of early cardiovascular disease in first-degree relatives, hypertension, and diabetes, among others.

Regarding the treatment of severe FH, the expert panel recommends high-intensity statin therapy (high-dose atorvastatin and rosuvastatin) and ezetimibe to reduce LDL cholesterol concentrations by 50% or more, although the ideal goal is to reduce levels to less than 100 mg/dL. In patients with advanced subclinical atherosclerosis, detected with a coronary artery calcium test or CT angiography, the ideal LDL cholesterol target is less than 70 mg/dL (although a 50% reduction is considered more realistic). Similar treatment goals are outlined for severe FH patients with clinical cardiovascular disease.    

If patients fail to meet the treatment targets, the panel recommends triple-therapy, which would include statin therapy, ezetimibe, and the addition of one of the two new PCSK9 inhibitors, either alirocumab (Praluent, Sanofi-Aventis/Regeneron Pharmaceuticals) or evolocumab (Repatha, Amgen). Bile-acid sequestrants or niacin would also be options for physicians looking to add a third agent.

And finally, if the patient with severe FH is still unable to reduce LDL cholesterol levels by more than 50% (or to reach the less than 70 or 100 mg/dL goals), physicians can consider adding lomitapide (Juxtapid, Aegerion Pharmaceuticals) or mipomersen (Kynamro, Genzyme/Isis Pharmaceuticals), two agents approved by the US Food and Drug Administration for homozygous FH.

The IAS panel acknowledges the financial cost of these medications, however, noting that the PCSK9 monoclonal antibodies are approximately $14,000 per year while mipomersen costs $176,000 annually and lomitapide can range between $235,000 to $295,000 per year. “Therefore, characterization of individuals at high risk, maximization of standard treatment use, and judicious use of those treatments by following a step-by-step protocol could attenuate these costs, as long as intensive reduction in LDL cholesterol reduces the risk of these events effectively,” they write.