Familial hypercholesterolemia (FH) is a genetically inherited disorder of alleles involved in low-density lipoprotein cholesterol (LDL-C) uptake and metabolism; it confers an increased risk of atherosclerotic cardiovascular disease (ASCVD) and mortality.^1,2 However, ASCVD risk in FH patients varies greatly, and better understanding this spectrum of risk may allow for tailoring treatment especially regarding the need for a PCSK9 inhibitor. Recently released work from large FH patient registries offers additional data on risk stratification in FH, with important implications for patients and practitioners working with this population.

Characterizing Risk in FH

FH is generally diagnosed in childhood, adolescence or young adulthood either via genetic testing or clinical phenotype, with an LDL-C ≥190 mg/dL after dietary modifications or an LDL-C ≥160 mg/dL with a family history of early ASCVD indicating a high likelihood of FH.^3,4 As an autosomal dominant disease, it is estimated one in 250-500 are heterozygotes for the disease in the general population, with an even higher prevalence in founder regions such as Northern Europe.^5-7 Homozygous FH is observed much more rarely, with estimates ranging from one in 160,000-1,000,000; it presents with a much more significant disease phenotype than in heterozygous patients.^8,9

For the purposes of ASCVD risk stratification, the International Atherosclerosis Society (IAS) released an expert consensus in 2016 suggesting that FH patients be further characterized specifically as severe and non-severe FH. In those untreated and at first presentation, severe FH is defined by the IAS as either LDL-C >400 mg/dL, LDL-C >310 mg/dL with one high-risk feature, or LDL-C >190 mg/dL with two or more high-risk features (high-risk features listed in Table 1).¹ Additional inclusion criteria for severe FH are advanced subclinical ASCVD (defined as a coronary artery calcium score >100 Agatston units and/or >75th percentile, or CT angiography with at least one >50% obstructive lesion or multi-vessel lesions <50%) or clinical ASCVD (defined as a previous cardiac event, transient ischemic attack, stroke or intermittent claudication).

Table 1: IAH Risk Factors in FH

Age > 40 years without treatment Male sex Smoking Lipoprotein(a) >50mg/dL HDL <40 mg/dL Diabetes mellitus History of early CAD first-degree relative (<55 years in men, <60 years in women) BMI >30kg/m2 CKD (GFR <60mL/min)

Aside from stratifying patients with respect to risk, these criteria ultimately have important implications on therapeutic recommendations.¹ For example, patients with severe FH are recommended by the IAS to reduce LDL-C by >50% overall and ideally to <100 mg/dL (and <70 mg/dL in those with advanced subclinical or known ASCVD) starting with high-intensity statin alongside ezetimibe. If the LDL-C is still not at goal, the guidelines recommend adding a PCSK9 inhibitor with advanced therapies following if not at goal with this regimen (see Table 2 for full IAS treatment recommendations).

Table 2: IAS Treatment Recommendations for FH

All patients: Lifestyle and dietary modifications, high-intensity statin plus ezetimibe → LDL-C <50% reduction or not at goal: Add PCSK9 inhibitor or niacin/bile acid sequestrant pending available and cost → LDL-C <50% reduction or not at goal: Consider lipid apheresis, lomitapide, mipomersen, or liver transplant

Evaluating the IAS Definitions

IAS recommendations have been challenged by some as not appropriately assessing ASCVD risk by relying primarily on cross-sectional and retrospective studies.¹⁰ This debate has been placed in even more acute focus by the cost associated with IAS recommended therapies, such as PCSK9 inhibitors, and recent work on the benefits derived in non-FH population when implementing these therapies.^11,12

Humphries et al. attempted to evaluate the IAS definition's applicability via objective outcome measurement in the large Simon Broome Registry.¹³ In a cohort prospectively followed between 1992 and 2016, 2,929 patients were separated into severe and non-severe FH, as described by the IAS criteria. In total, 68% of patients met IAS definitions for severe FH. The standardized mortality ratio was 64% (p = 0.007) higher in patients with severe FH than non-severe FH (SMR 220 (184-261) versus 144 (98-203) in severe and non-severe FH, respectively).

Interestingly, this excess coronary heart disease mortality risk in patients with severe FH was no longer present after adjustment for a history of coronary heart disease, total cholesterol, age, sex \and smoking history (HR 1.22 [0.80-1.87], p = 0.36). This suggests that early attention to risk factor modification in FH patients, such as smoking cessation, may reduce morbidity and mortality in this population.¹³

The Humphries et al. study suggests that characterization of patients by IAS definitions may lead to reductions in ASCVD risk and cardiac events via the implementation of appropriate treatment regimens, though notably without direct evaluation of the pharmacotherapies suggested by IAS guidelines. The authors highlight that during a 2010 audit of 2,328 patients in the registry, 86% were noted to be on statin therapy and 40% on ezetimibe, suggesting that mortality remained high despite treatment efforts.¹³ This may be due to delayed initiation of lipid lowering therapy, as well as inadequate control of non-lipid ASCVD risk factors.

The SAFEHEART (Spanish Familial Hypercholesterolaemia Cohort Study) registry of 2,752 patients, with molecularly diagnosed FH, also showed low levels of treatment success. Only 11% of patients reached optimal LDL-C values on maximum lipid-lowering therapy.¹⁵ Importantly, neither of these studies evaluated the effect of IAS guideline treatment recommendations; further studies are thus in this regard.

Conclusion

Recent work by Humphries has added support for the existing definitions of ASCVD risk in FH patients. Outside of the Simon Broome and the SAFEHEART registries, FH cohorts remain small, despite an estimated >20 million patients with FH globally. Improved identification of FH patients and their participation in larger studies will help to better understand heterogeneity of risk in this population. In addition to exposure to non-lipid risk factors, heterogeneity in risk may relate to the underlying severity of the FH causing mutation. Of note, the Simon Broome registry did not molecularly diagnose patients, sbut doing so adds confidence in the diagnosis and may aid in risk stratification.¹⁴ In our opinion, modern registries should push for molecular diagnosis, as we are beginning to see with the CASCADE FH (Study of Awareness and Detection of Familial Hypercholesterolemia) registry in the US.

In summary, a growing body of evidence points toward the IAS definitions as a strong benchmark from which further guidelines can build. In the interim, they provide an important opportunity for clinicians to reduce cardiac events and improve the lives of their patients with FH by focusing on LDL-C control along with comprehensive risk factor modification.

References

1. Santos RD, Gidding SS, Hegele RA, et al. Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. Lancet Diabetes Endocrinol 2016;4:850-61.
2. Defesche JC, Gidding SS, Harada-Shiba M, Hegele RA, Santos RD, Wierzbicki AS. Familial hypercholesterolaemia. Nat Rev Dis Primers 2017;3:17093.
3. Wiegman A, Gidding SS, Watts GF, et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J 2015;36:2425-37.
4. Gidding SS, Champagne MA, de Ferranti SD, et al. The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association. Circulation 2015;132:2167-92.
5. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Study. Eur Heart J 2013;34:3478-90.
6. Lahitnen AM, Havulinna AS, Jula A, Salomaa V, Kontula K. Prevalence and clinical correlates of familial hypercholesterolemia founder mutations in the general population. Atherosclerosis 2015;238:64-9.
7. de Ferranti SD, Rodday AM, Mendelson MM, Wong JB, Leslie LK, Sheldrick RC. Prevalence of familial hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES). Circulation 2016;133:1067-72.
8. Raal FJ, Sjouke B, Hovingh GK, Isaac BF. Phenotype diversity among patients with homozygous familial hypercholesterolemia: a cohort study. Atherosclerosis 2016;248:238-44.
9. Sanchez-Hernandez RM, Civeira F, Stef M, et al. Homozygous familial hypercholesterolemia in Spain: prevalence and phenotype-genotype relationship. Circ Cardiovasc Genet 2016;9:504-10.
10. Perez-Calahorra S, Sanchez-Hernandez RM, Plana N, et al. Value of the definition of severe familial hypercholesterolemia for stratification of heterozygous patients. Am J Cardiol 2017;119:742-8.
11. Hlatky MA, Kazi DS. PCSK9 inhibitors: economics and policy. J Am Coll Cardiol 2017;70:2677-87.
12. Kazi DS, Penko J, Coxson PG, Guzman D, Wei PC, Bibbins-Domingo K. Cost-effectiveness of alirocumab: a just-in-time analysis based on the ODYSSEY Outcomes trial. Ann Intern Med 2019. [Epub ahead of print]
13. Humphries SE, Cooper JA, Capps N, et al. Coronary heart disease mortality in severe vs. non-severe familial hypercholesterolaemia in the Simon Broome Register. Atherosclerosis 2019;218:207-12.
14. Tada H, Kawashiri MA, Nohara A, Inazu A, Mabuchi H, Yamagishi M. Impact of clinical signs and genetic diagnosis of familial hypercholesterolaeamia on the prevalence of coronary artery disease in patients with severe hypercholesterolaemia. Eur Heart J 2017;38:1573-9.
15. Perez de Isla L, Alonso R, Watts GF, et al. Attainment of LDL-cholesterol treatment goals in patients with familial hypercholesterolemia: 5-year SAFEHEART registry follow-up. J Am Coll Cardiol 2016;67:1278-85.

Clinical Topics: Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Vascular Medicine, Advanced Lipid Testing, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: Dyslipidemias, Hypercholesterolemia, Hyperlipoproteinemia Type II, Risk Factors, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Retrospective Studies, Smoking Cessation, Liver Transplantation, Oligonucleotides, Benzimidazoles, Coronary Disease, Blood Component Removal, Registries, Life Style, Lipids, Cholesterol, Cholesterol, LDL, Ischemic Attack, Transient, Lipoprotein(a), Heterozygote, Intermittent Claudication, Coronary Vessels, Atherosclerosis, Stroke, Body Mass Index, Homozygote, Phenotype, Diabetes Mellitus, Renal Insufficiency, Chronic

< Back to Listings