Undiagnosed FH Linked to 16-Year Life Expectancy Reduction

Liam Davenport

June 06, 2019

MAASTRICHT, The Netherlands — People with probable but undiagnosed familial hypercholesterolemia (FH) have a higher rate of premature death from cardiovascular events than those who have been diagnosed with the disease, translating into a reduction of life expectancy averaging 16 years, say British researchers.

Kausik K. Ray, MD, PhD, Imperial Centre for Cardiovascular Disease Prevention, Imperial College London, and colleagues studied data from a large primary care database on almost 1.8 million individuals, of whom nearly 7000 had been diagnosed with FH and more than 13,000 probably had the disease.

Presenting the results at the European Atherosclerosis Society 2019 Congress, Ray showed that individuals with probable FH were 1.9 times more likely to suffer premature cardiovascular-related death than those diagnosed with the disease.

They were also 2.4-fold more likely to die early from cardiovascular events than people who had normal low-density-lipoprotein (LDL)-cholesterol levels and so were unlikely to have FH.

The researchers also showed that, of the premature cardiovascular deaths due to increased LDL-cholesterol levels, 56% occurred in individuals with undiagnosed FH.

Ray emphasized that, while coding and diagnosing FH continue to be a "challenge," the current results show, "within the limitations of big data," that individuals "who do not have a diagnosis behave very similarly to those patients in whom a diagnosis is achieved."

However, undiagnosed individuals "lose essentially 16 years of life by the age of 18 if the diagnosis is not made."

"We think that really supports the case for screening much earlier and thinking about cholesterol screening before the age of 20," Ray said.

He added that they observed geographic variations in FH testing, "which is unlikely to be truly a real biological variation but likely the effect of policy, and this gets at the importance of policy toward FH screening and detection."

Geesje M. Dallinga-Thie, PhD, manager, Laboratory of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, who cochaired the session, questioned the need for FH genetic diagnoses, however.

She told theheart.org | Medscape Cardiology that, in her experience, doctors do not treat on that basis, as was shown in the study by the use of statins being "very high" in non-FH individuals.

"That makes sense, because doctors treat the cholesterol and, in principle, it shouldn't make any difference."

Confirmed Diagnosis

The global prevalence of FH is estimated to be one in 200 to 300, but it is widely underdiagnosed and undertreated, Ray said during his presentation. Moreover, it is known that treatment of FH with lipid-lowering therapies reduces the associated cardiovascular risk.

What is unknown, however, is whether outcomes differ between individuals with a confirmed FH diagnosis and those with potential but undiagnosed disease.

The researchers therefore conducted a retrospective study in which they gathered data on 5,672,532 adults registered in the UK Clinical Practice Research Datalink database between 2008 and 2013.

From those, they identified 1,729,046 individuals who either had a diagnosis of FH in the database or had a recorded LDL-cholesterol measurement, and had no history of cardiovascular disease.

Among these, 6843 had a diagnostic FH code, termed "FH coded," and 13,459 were categorized as having probable FH, or "FH potential."

This was defined as at least one LDL-cholesterol measure indicating "definite" or "probable" FH on the modified Dutch Lipid Clinic Network Score or EUROASPIRE criteria.

The remaining 1,707,744 individuals were classified as "FH unlikely."

Ray noted that the average age of FH-coded individuals was less than that of FH-potential or FH-unlikely individuals (50.9 vs 60.8 vs 62.2 years).

FH-coded patients were also more likely to be white than the other two groups (52.9% vs 32.8% vs 32.6%).

Across the United Kingdom, the prevalence of FH-coded individuals was far higher in Wales than in England, Scotland, and Northern Ireland, which Ray said reflects an aggressive drive in that region to diagnose FH.

The body mass index of FH patients was also lower than that recorded in FH-potential and FH-unlikely individuals, with a lower proportion of overweight and obese individuals.

In contrast, FH-potential individuals were more likely than either FH-coded and FH-unlikely participants to be current smokers and to have diabetes and hypertension.

They were also more likely than either group to have received a statin prescription (67.5% vs 33.3% for FH-coded and 23.9% for FH-unlikely individuals). A similar pattern was seen with intensive statin therapy.

Unsurprisingly, FH-coded patients had their first recorded LDL-cholesterol measurement at a younger average age than FH-potential individuals.

Next, the team examined the risk of experiencing a cardiovascular event, defined as fatal or nonfatal unstable angina, acute MI, ischemic stroke, transient ischemic attack, coronary revascularization, or peripheral artery disease.

FH-coded and FH-potential individuals had higher age-specific cardiovascular event incidence rates and a lower age at first cardiovascular event than FH-unlikely participants.

This translated into an overall hazard ratio of a cardiovascular event in FH-coded versus FH-unlikely individuals of 1.97 (< .001).

The risk for a cardiovascular event was only slightly lower in FH-potential than in FH unlikely individuals (hazard ratio, 1.89; P < .001).

In both cases, the risk was broadly comparable between men and women.

Ray noted that the risk for a cardiovascular event became significant in the 40- to 44-year age bracket for both FH-coded and FH-potential individuals, at respective hazard ratios of 2.99 (P < .001) and 3.29 (P = .002).

Overall, the risk for premature cardiovascular events, defined as occurring before 55 years in males and 60 years in females, was higher in both FH-coded and FH-potential individuals than in FH-unlikely individuals, at hazard ratios of 1.97 and 1.89, respectively (< .001 for both).

FH-potential individuals, however, had a significantly greater risk for premature cardiovascular events than both FH-potential and FH-unlikely participants when performing age- and gender-standardized analyses per 100,000 people.

FH-potential individuals, however, had a significantly greater risk of premature cardiovascular events than both FH potential and FH unlikely participants when performing age- and gender-standardized analyses per 100,000 persons.

After the exclusion of individuals with diabetes and hypertension, the researchers found that the relative risk for premature events in FH-potential individuals compared with FH-coded participants was 1.88 (P = .002), and compared with FH-unlikely individuals was 2.40 (P < .001).

Using the Chiang II method, the researchers calculated that this translated into a reduced life expectancy in FH-potential versus FH-coded individuals of 16 years at 18 to 19 years, which continued well into their 30s.

The team calculated that, excluding smokers and individuals with diabetes and hypertension, 44% of all premature deaths associated with increased LDL-cholesterol levels occurred in coded-FH patients and 56% occurred in FH-potential individuals.

Argues Against Screening?

During the postpresentation discussion, Ray was asked whether the lower rate of statin use in the FH-coded group than in the FH-probable group "argues against" the call for screening.

He replied that the study does not take into account the treatment trajectory of participants in the database, and that previous studies have shown that receiving a diagnosis of FH leads to lifestyle changes at an earlier age.

However, Ray emphasized that there are limitations as to what one "can and can't do" with the analysis, "because you can't check behavior and adherence."

An audience member also pointed out that young people have a high degree of intra-individual variability in lipid levels, "so you can’t get away with one measure of LDL cholesterol."

He observed: "We'd need to do several measurements, and that doesn't tend to work out very well."

Ray responded that, although genetic testing will never be universally available, LDL-cholesterol measurements could be used as a "prescreen, and the earlier you do that, the earlier behavior, lifestyle, and other things might change."

The study was funded by Amgen. Ray reports research grants from Amgen, Sanofi, Regeneron, MSD, Pfizer; consultancy for Amgen, Sanofi, Regeneron, MSD, Pfizer, AstraZeneca, Lilly, The Medicines Company, Kowa, IONIS, Takeda, Novo Nordisk, Boehringer Ingelheim, Esperion Therapeutics, Cipla, Algorithm, Resverlogix, and Cerenis. Other authors report several potential conflicts of interest.

European Atherosclerosis Society (EAS) 2019 Congress: Abstract EAS19-1126. Presented 27 May, 2019.

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