In South Africa, FDCs ezetimibe/atorvastatin is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in patients living with primary (heterozygous FH [HeFH] and non-familial) hypercholesterolaemia. It is also indicated for patients as adjunctive therapy to diet in adult patients living with homozygous FH (HoFH), to reduce elevated total-C and LDL-C levels.¹

Hypercholesterolaemia affects ~11.9% of adults, corresponding to around 28.5 million individuals ≥20-years, and is defined as LDL-C >4.9mmol/l, >4.1mmol/l with one major cardiovascular (CV) risk factor, or >3.3mmol/L with two CV risk factors.^2,3

Risk factors contributing to hypercholesterolaemia include age, family history of premature coronary artery disease (CAD), hypertension, diabetes, smoking, and low high-density cholesterol (HDL-C) levels.^3,4

What is familial hypercholesterolaemia?

FH is a genetic disorder and is frequently underdiagnosed and undertreated due to a lack of awareness among clinicians and the public. Individuals with untreated FH face a 20-fold higher likelihood of developing CV disease (CVD) compared to those without FH.⁴

FH can manifest as HeFH or HoFH, arising from one or two pathogenic variants in genes such as the LDL receptor, apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 (PCSK9). HoFH is rare (~30 000 cases worldwide, but <5% are identified) and is characterised by severely elevated LDL-C levels from birth and accelerated CAD, making it a life-threatening condition.^3,4,5,6

HeFH, on the other hand, is the most common (1:250) genetic disease in humans and will therefore be the focus of the rest of the article.⁵

How is FH diagnosed?

FH diagnosis is based on cholesterol levels, early CAD onset, and family history. FH should be suspected in adult patients with LDL-C levels ≥4.9mmol/l, and children (<20-years) with LDL-C levels ≥4.1mmol/l. The higher the LDL-C value, the more suggestive of FH.⁴

Early lipid screening (from the age of two) is recommended in children with a family history of early onset CAD (men <55-years, women <65-years), a parent with a total-C >6.2mmol/l, if they have underlying cardiac risk factors (eg diabetes or obesity) or tendon xanthomas.^7,8

Screening between the ages of nine- to 11-years enables the best discernment between those with and without FH and avoids confounding lipid changes secondary to LDL‐C reduction, known to transiently occur during puberty.⁷

The International Atherosclerosis Society underscores that paediatric diagnosis of FH should ideally involve lipidology-trained pediatricians. In challenging fasting situations, a non-fasting blood sample might suffice for clinical diagnosis. Genetic testing, particularly for index patients with a phenotypic diagnosis, is encouraged to facilitate cascade testing.⁸

Management of HeFH

The first goal of management is to reduce LDL-C by at least 50%. Dietary and lifestyle modifications are the starting points in patients living with FH. Statins are the cornerstone of pharmacotherapy, but multi-drug treatment is often required to achieve adequate LDL‐C levels. CVD risk factors and comorbidities, such as hypertension and diabetes, should be treated.⁴

Several guidelines recommend treatment with statins in children and adolescents (eight- to ≥10-years) who have a persistent LDL‐C ≥4.1mmol/L after three to six months of lifestyle modification, and a clinical presentation consistent with FH.⁷

Furthermore, ezetimibe is approved by the American Food and Drug Administration for the treatment of patients with HeFH without age restrictions, but data have not been reviewed for children <10-years, or premenarchal girls.⁷

The American College of Cardiology/American Heart Association guidelines recommend lipid‐lowering therapies for patients with a baseline LDL‐C level of ≥4.9mmol/l and include specific recommendations for patients with FH.

Given that many patients with FH have documented CAD and will continue to be at very high risk for future CV events, guidelines suggest the use of an LDL‐C threshold of 1.8mmol/l for the addition of non-statins to statin therapy. Non-statins include ezetimibe, bile acid sequestrants, and PCSK9 inhibitors.⁷

How effective is combination therapy?

According to the European Atherosclerosis Society, only ~12% of patients reach LDL-C targets. Ballantyne et al state that factors that contribute to this include inadequate dosing, increased risk for adverse effects with high-dose monotherapy, and increased potential for intolerance and adverse effects with combinations of available agents.^6,9

Ballantyne et al conducted a double-blind study in patients (n=628) with baseline LDL-C 3.7mmol/l to 6.4mmol/l 250 and triglycerides ≤9mmol/l were randomly assigned to receive ezetimibe (10mg/d), atorvastatin (10mg/d, 20mg/d, 40mg/d, or 80mg/d), ezetimibe (10mg) plus atorvastatin (10mg/d, 20mg/d, 40mg/d, or 80mg/d) or placebo for 12 weeks. The primary efficacy endpoint was percentage reduction in LDL-C for pooled ezetimibe plus atorvastatin versus pooled atorvastatin treatment groups.⁹

The authors found that ezetimibe plus atorvastatin significantly improved LDL-C, HDL-C, triglycerides, and total cholesterol compared with atorvastatin alone. Co-administration of ezetimibe provided a significant additional 12% LDL-C reduction, 3% HDL-C increase, 8% triglyceride reduction versus atorvastatin alone.⁹

Ezetimibe plus atorvastatin provided LDL-C reductions of 50% to 60%, triglyceride reductions of 30% to 40%, and HDL-C increases of 5% to 9%, depending on atorvastatin dose. LDL-C reductions with ezetimibe plus 10mg atorvastatin and 80mg atorvastatin alone were similar.⁹

Conclusion

Treatment initiation, involving high-intensity statin, ezetimibe, and lifestyle measures, is recommended as early as possible to reduce the risk of CVD. The use of fixed-dose combination ezetimibe/atorvastatin therapy has shown promising results, with significant reductions in LDL-C, HDL-C, triglycerides, and total cholesterol.

 References

1. Professional Information. Ezetimibe/Atorvastatin. [Internet]. 2022. Available at: https://pi-pil-repository.sahpra.org.za/wp-content/uploads/2023/04/Final_PI_-Dytorez_Applicant.pdf
2. Benjamin EJ, et al. Heart disease and stroke statistics - 2018 update: A report from the American Heart Association. Circulation. 2018
3. Ibrahim MA, Asuka E, Jialal I. [Updated 2023 Apr 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459188/
4. Onorato A, Sturm AC. Heterozygous Familial Hypercholesterolemia. Circulation, 2016.
5. Di Taranto MD, Fortunato G. Genetic Heterogeneity of Familial Hypercholesterolemia: Repercussions for Molecular Diagnosis. Int J Mol Sci, 2023.
6. Cuchel M, et al. 2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance. European Heart Journal, 2023.
7. McGowan MP, et al. Diagnosis and Treatment of Heterozygous Familial Hypercholesterolemia. JAHA, 2019.
8. Watts GF, et al.International Atherosclerosis Society guidance for implementing best practices in the care of familial hypercholesterolaemia. Nat Rev Cardiol, 2023.

Ballantyne CM, et al. Ezetimibe Study Group. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation, 2003.