More people may be diagnosed with familial hypercholesterolemia (FH) using criteria contained in a new scientific statement published by the American Heart Association. The expanded definition could also mean more patients will be eligible to receive expensive cholesterol-lowering drugs, including the new PCSK9 inhibitor drugs, (Repatha from Amgen and Praluent from Sanofi/Regeneron).
But the biggest impact might be to increase the market for two other extremely expensive drugs approved exclusively for use in the rare but often extremely serious condition of homozygous FH, Juxtapid (lomitapide, Aegerion) and Kynamro (mipomersen, Genzyme). For these drugs even a small increase in eligible patients could have an enormous impact, since the drugs have a sticker price between $150,000 and $250,000 a year (though the actual cost may often be lower).
Samuel Gidding (Thomas Jefferson University Hospital), the chairman of the committee that wrote the scientific statement, said that the committee did not intend to expand the clinical definitions of FH: “We wished to provide a “road map” among clinical criteria, genetic testing results, and the “hopefully” future ICD-10 codes to help providers. We also wanted to make a strong statement in favor of LDL-c level as a driver of treatment intensity as opposed to requiring genotypic proof of homozygosity.
But Marilyn Mann, a respected and highly knowledgeable FH patient advocate, is concerned about the new AHA statement. “The diagnostic criteria for heterozygous and homozygous FH proposed in the AHA scientific statement will increase the number of people diagnosed with FH, but I’m worried that a lot of those people won’t actually have FH. Could lead to some good, but also some not so good. They seem to have opted for high sensitivity but low specificity. You could have people with age-related and lifestyle-related LDL elevations get diagnosed with FH.”
The new criteria for heterozygous FH sets an LDL level of at least 190 mg/dL for adults who have a similarly affected first-degree relative, premature coronary artery disease, or a positive genetic test. According to Mann, 3% of the population has LDL levels over 190 mg/dL level, but, she points out, “less than 1% of the population has FH. You could have docs diagnosing people with HeFH or HoFH solely so that their insurance will cover a medication, such as PCSK9 inhibitors. That could be very confusing for patients.”
For homozygous FH the AHA statement establishes 400 mg/dL as the new lower level, but, observes Mann, “traditionally 500 mg has been the LDL level for a clinical diagnosis of HoFH. They are lowering it to 400 to capture people with 1 or 2 FH mutations who have levels in the 400s, so that those people can get lomitapide or mipomersen.”
James Stein (University of Wisconsin) agrees with Mann’s concerns:
“If you change the definition of the disease so the threshold for diagnosing it is lower, you increase the risks of (i) mislabeling people and (ii) creating more ‘diseased’ people. As important, you inevitably will pick up less sick people and therefore lower the risk of having the disease, especially when a disease is heterogeneous, like FH. Indeed, FH is so heterogenous in its phenotype, genotype, and penetrance, I’d argue we should get rid of the diagnosis altogether. Even the name is bad – ‘familial hypercholesterolemia’- it sounds like everyone with a family history of high cholesterol has it or is at risk for it, when it is a rather uncommon disorder. But more important, it is the phenotype, not the genotype that drives risk of FH, so the need for genetic testing (other than for genetic counseling) remains very unclear to me. I have been a lipid doc for nearly 20 years and never once said, about a high cholesterol patient, that “I really need to know the gene this patient has” in order to optimally treat him or her.”