Absence of FH Diagnosis Linked to Increased Risk of Premature Mortality

MAASTRICHT, the Netherlands—Individuals with significantly elevated LDL cholesterol levels suggestive of familial hypercholesterolemia (FH) are nearly twice as likely to die prematurely when compared with people who have a definitive FH diagnosis, according to the results of a new analysis.

Researchers say that individuals with FH who are not diagnosed early—by age 18—lose nearly 16 years of life compared with those who receive a coded diagnosis. “Age 40 or 50 is too late to make a diagnosis when FH is present from birth,” lead investigator Kausik Ray, MD (Imperial College London, England), told TCTMD.

As for the solution? “Universal screening for cholesterol before the age of 20,” said Ray, who presented the results at the European Atherosclerosis Society Congress 2019.

“Most countries don’t do it,” he continued. “With phenylketonuria, say, if you don’t do something in the first couple of years, there can be permanent problems, but it’s very rare. Here, FH is much more common, and if you do something about it you might actually have a bigger impact. But because the effect is cumulative—nothing much is happening in the first 20 years, it’s the 20 years after—the government doesn’t see the gains.”

Heterozygous FH, which is associated with lifelong exposure to elevated cholesterol levels and an increased risk of premature cardiovascular disease, occurs in roughly one out of every 200 to 300 people in the general population. While the case for universal screening by the age of 20 is “fairly intuitive,” Ray said, the argument for it would be stronger if physicians had data on whether such screening improved clinical outcomes in individuals with a definitive, coded diagnosis for FH.

More Than 1.7 Million Patients in CPRD

Given that a trial of screening versus no screening would be extremely difficult to do, the researchers set out to evaluate outcomes based on FH diagnoses. They conducted a large, retrospective cohort study using data from the United Kingdom Clinical Practice Research Datalink (CPRD) registry and identified three different patient groups: 1) patients with a coded diagnosis of FH (n = 6,843); 2) potential patients who met the criteria for FH using modified criteria from the Dutch Lipid Clinic Network but who were not diagnosed (n = 13,459); and 3) patients without a diagnosis of FH and not likely to have FH (n = 1,707,744). None had a prior history of cardiovascular disease.

In their study, premature atherosclerotic cardiovascular disease (ASCVD) was defined as unstable angina, acute MI, ischemic stroke, TIA, coronary revascularization, and PAD occurring before age 55 in men and 60 in women.

Individuals with a coded FH diagnosis were approximately 10 years younger than those with potential FH and were less likely to be diagnosed with diabetes and hypertension. They were also less likely to smoke and less likely to be overweight or obese. Kay said this makes sense given that these patients are aware of their diagnosis and might have altered their behavior. One-third of the FH-coded patients were treated with a statin, including 11% on high-intensity therapy, compared with 67.5% of the patients with potential FH and 23.9% of patients without FH.

Speaking during the presentation, Ray noted that people with an FH diagnosis had their first LDL cholesterol measurement taken earlier in life. Regarding incident events, the age-specific cardiovascular event rate was lowest in patients without FH and highest in those with an FH diagnosis. For patients without FH, incident cardiovascular events occurred roughly 10 years later than those with coded FH, he added.

In terms of relative risk, coded FH carried a twofold greater risk of cardiovascular events compared with no FH (RR 1.97; 95% CI 1.82-2.12). People with potential FH had a risk of similar magnitude when compared with those without the genetic lipid disorder (RR 1.79; 95% CI 1.79-1.99). The similar risk of incident ASCVD among the definitive and potential FH patients supports the research team’s use of elevated LDL cholesterol as a proxy for potential FH and strengthens the probability these individuals had the genetic condition, according to Ray.  

With respect to mortality, the absence of an FH diagnosis was associated with worse outcomes. For example, those with potential FH had an 88% increased risk of death compared with individuals with a coded FH diagnosis after excluding patients with diabetes and hypertension (RR 1.88; 95% CI 1.27-2.78). For those with potential FH, the excess mortality risk was even greater compared with those without FH after excluding the diabetes and hypertension subgroups (RR 2.40; 95% CI 1.57-3.67).

High Variability in LDL Cholesterol Levels in Young People

Ray pointed out that individuals might have received a diagnosis of FH but the information might not be documented in their medical record. Nonetheless, these new data suggest that early screening to diagnose patients with FH can prevent premature ASCVD deaths.

Robert Cramb, MD (University Hospitals Birmingham NHS Foundation Trust, England), who was not involved in the study, said there has been a fairly concerted “anti-statin” movement in the United Kingdom. As a result, even some physicians have shied away from treating LDL cholesterol levels. “They forget that FH is a relatively common disease,” Cramb told TCTMD. “If you find it, you can then treat not just one person but families. That’s the big problem in the UK: trying to get that message across.”

Cramb noted that Wales launched an FH cascade testing service in 2010, a strategy aimed at identifying and increasing the awareness of FH in primary care. It also promoted access to specialist FH services, including genetic testing and cascade family testing. Interestingly, in the CPRD data presented by Ray, 1,325 of the 6,843 patients identified with coded FH were from Wales, and Wales had a higher prevalence of coded FH than Northern Ireland, an area similar in size and population. This likely reflects the more aggressive screening program in Wales, according to Cramb and Ray.

One caution about screening for FH in young adults is that there can be high intraindividual variability in this population, said Cramb. Use of capillary samples, or blood spot measurements, proposed by Nicholas Wald, MBBS (Queen Mary University of London, England), as a method to screen for FH in young children during routine immunization, also results in a high coefficient of variation.

“So while I like the concept, you may miss people with this, and you may test more people who wouldn’t necessarily have a higher cholesterol concentration but it’s just that you’ve picked them up at a high point,” said Cramb. “False negatives and false positives are much more likely. The same also applies for adolescents.”

Cramb, who is a proponent of early screening for FH, said that one measurement for a single individual is not sufficient. To screen and do it well, at least three cholesterol tests are needed to get an accurate measurement, he advised.

Stateside, the United States Preventive Services Task Force (USPSTF) updated its recommendations in 2016 and now focuses on a preventive medication framework rather than on screening in order to identify adults who would benefit from statin therapy. The USPSTF states that adults aged 40 to 75 years should undergo lipid screening to determine their risk of cardiovascular disease and recommends statins for primary prevention in those with one or more risk factors and a 10-year event risk 10% or greater. For those younger than 40 years, the task force says there is insufficient evidence for statins.

Correction: An earlier version of this story incorrectly characterized the USPSTF’s cholesterol screening recommendations. The USPSTF updated the recommendations in 2016 to focus on preventive statin use in eligible patients.