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. 2023 Sep 6:15:100580.
doi: 10.1016/j.ajpc.2023.100580. eCollection 2023 Sep.

Premature morbidity and mortality associated with potentially undiagnosed familial hypercholesterolemia in the general population

Kausik K Ray  1 , Demetris Pillas  2 , Savvas Hadjiphilippou  1 , Kamlesh Khunti  3 , Sreenivasa Rao Kondapally Seshasai  4 , Antonio J Vallejo-Vaz  1   5   6 , David Neasham  2 , Janet Addison  7
Affiliations

Premature morbidity and mortality associated with potentially undiagnosed familial hypercholesterolemia in the general population

Kausik K Ray et al. Am J Prev Cardiol. .

Abstract

Background: Familial hypercholesterolemia (FH) is common, but underdiagnosed, and few systematic early screening programs exist.

Objective: To assess health outcomes among those with a recorded diagnosis of FH and potential cases of FH with no recorded diagnosis.

Methods: Retrospective cohort study using the UK Clinical Practice Research Datalink. Records of adults were classified as diagnosed FH (FHCoded), or via accepted algorithms using LDL-C and clinical characteristics as potential FH (FHPotential) or unlikely FH (FHUnlikely) using the DLCN or EUROASPIRE criteria (but no record of FH). Outcomes assessed were premature cardiovascular (CV) events, premature deaths and life expectancy.

Results: Among 1,729,046 individuals free from CV events, a record of FHCoded before the age of 40 was 0.3/1000 (IQR 0.3-0.4) and increased with age. Where LDL-C levels were available, 1.8/1000 (IQR 1.6-2.0) could be classified as FHPotential. LDL-C was higher for both FHCoded and FHPotential vs FHUnlikely (185.6 and 216.6 vs 116 mg/dL, respectively, p<0.001). Compared to FHUnlikely both FHCoded and FHPotential cohorts had a higher risk of premature cardiovascular events (both p<0.001) with highest rates among FHCoded. Risk of premature deaths did not differ between FHCoded and FHUnlikely, but was 1.88 (95% CI 1.27-2.78, p = 0.002) for FHPotential vs FHCoded and 2.40 (95% CI 1.57-3.67, p<0.001) for FHPotential vs FHUnlikely. At age 18, the FHPotential cohort had a life expectancy 16 years lower than the FHCoded cohort (p<0.001).

Conclusions: Potential cases of FH had a doubling in risk of premature death and a large reduction in life expectancy compared to individuals with a recorded diagnosis of FH. These findings strengthen the critical importance of identifying potential cases of FH early and early treatment.

Keywords: Cardiovascular disease prevention; Familial hypercholesterolemia; LDL-C; Screening.

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Conflict of interest statement

Professor Kausik K. Ray reports the following; Unrestricted research grants to Imperial College London from Amgen, Daiichi Sankyo, Regeneron, Sanofi, SC, EC or advisory boards honoraria from Novartis, Esperion, Daiichi Sankyo, Abbott, Bayer, Eli Lilly, Silence Therapeutics, CSL Behring, New Amsterdam Pharma, Sanofi, Amgen, Novo Nordisk, BI, Scribe, Vaxxinity, CRISPR, AZ, Kowa, Cargene, Honoria for CME and non CME from Novartis, Novo Nordisk, BI, AZ, Viatris, Daiichi Sankyo, Amgen, Sanofi and stock options PEMI-31. Dr. Demetris Pillas provided consultancy services to Amgen Ltd. Dr. Savvas Hadjiphilippou has no disclosures. Professor Kamlesh Khunti has received research grants from Lilly, Sanofi-Aventis, Boehringer Ingelheim, Merck, Sharpe & Dohme, and Novo Nordisk, has provided consultancy services to Amgen, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Servier, and Merck, Sharpe & Dohme, has served in non-remunerative positions of influence at Lilly, Sanofi-Aventis, Merck, Sharpe & Dohme, and Novo Nordisk and has participated in Speakers Bureau for Lilly, Sanofi-Aventis, Merck, Sharpe & Dohme, and Novo Nordisk. Dr. Sreenivasa Rao Kondapally Seshasai has provided consultancy services to Amgen. Dr. Antonio J. Vallejo-Vaz reports current or past participation in research grants to Imperial College London from Pfizer, Amgen, MSD, Sanofi-Aventis, Daiichi Sankyo, and Regeneron; personal fees for consulting from Bayer and Regeneron; and honoraria for lectures from Amgen, Mylan, Akcea, and Ferrer; all outside the submitted work. Dr David Neasham is employed at Amgen Ltd. Ms. Janet Addison was previously employed at Amgen Ltd.

Figures

Fig 1
Fig. 1
The Timing of First Cholesterol Measurements by Age Across Cohorts. Panel A: Age at first LDL Cholesterol Measurement. Panel B: LDL Cholesterol Measurement by age. On average, the FHPotential cohort were 4.3 years (95% CI: 4.0–4.7, p<0.001) older than the FHCoded cohort at time of first recorded LDL-C measurement. Among the FHCoded cohort, 25% had a LDL-C record by the age of 45 and 50% by age 55. FH= Familial Hypercholesterolemia.
Fig 2
Fig. 2
The Occurrence of Cardiovascular Events by Age Across Cohorts. Panel A: Age-specific Cardiovascular Event Incidence Rate. Panel B: Age at First Cardiovascular Event. The age specific incidence of fatal and non-fatal cardiovascular events increased with age for all three cohorts and was highest for FHCoded and lowest for FHUnlikely within each age category. Of first cardiovascular events, 40.6% occurred by the age of 60 in the FHCoded cohort compared with 29.7% and 18.6% in the FHPotential and FHUnlikely cohorts, respectively (p<0.001). FH= Familial Hypercholesterolemia.
Fig 3
Fig. 3
Life Expectancy at a Given Age by Cohort. Panel A: Estimated Life Expectancy. Panel B: Estimated Reduction in Life Expectancy. Compared with the FHCoded cohort, life expectancy of individuals in the FHPotential cohort was one and a half decades lower (15.9 years, 95% CI:13.4–18.5 years) for those aged 18–19 years, one decade lower (10.1 years, 95% CI:7.9–12.2) for those aged 40–44 years, and approximately half a decade lower (4.5 years, 95% CI:3.0–5.9) for those aged 60–64 years. There were no significant differences in life expectancy between the FHCoded and FHUnlikely cohorts. FH= Familial Hypercholesterolemia.
Fig 4
Fig. 4
Central Illustration: Familial Hypercholesterolemia screening and diagnosis. Although familial hypercholesterolemia (FH) occurs in ∼1:300 individuals, few systematic screening programs exist. As a result, most cases of FH remain undiagnosed resulting in significant missed years of LDL exposure, and atherosclerotic burden. This increases the likelihood of subsequent premature cardiovascular disease and related morbidity and mortality. Patients with potentially undiagnosed FH have a two-fold increased risk of premature deaths with 16 years reduced life expectancy at age 18 compared to those with a confirmed diagnosis of FH. Early diagnosis and treatment is key to reducing the cardiovascular consequences of FH. CVD= cardiovascular disease, FH= Familial Hypercholesterolemia, He= Heterozygous, Ho= Homozygous, LDL= low density lipoprotein.
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