Elsevier

International Journal of Cardiology

Volume 345, 15 December 2021, Pages 119-124
International Journal of Cardiology

LDL cholesterol target achievement in heterozygous familial hypercholesterolemia patients according to 2019 ESC/EAS lipid guidelines: Implications for newer lipid-lowering treatments

https://doi.org/10.1016/j.ijcard.2021.10.024Get rights and content

Highlights

  • Most FH patients do not reach the latest 2019 ESC/EAS guidelines LDL-C targets.

  • Therapy with rosuvastatin/ezetimibe 40/10 mg/day shows small LDL-C target success.

  • Maximum statin/ezetimibe/PCSK9i combination greatly improves goal accomplishment.

  • Maximum statin/ezetimibe/PCSK9i combination is not enough for some patients.

Abstract

Background

The 2019 European guidelines (ESC/EAS) for the treatment of dyslipidaemias recommend more aggressive targets for low-density lipoprotein cholesterol (LDL-C) in patients with familial hypercholesterolemia (FH). Current lipid-lowering treatment is often inadequate to achieve these targets.

Methods

Data from the HELLAS-FH registry were analysed to assess achievement of LDL-C targets in adults with FH based on the 2019 ESC/EAS guidelines. In patients who had not achieved LDL-C target, the maximally reduced LDL-C value was calculated after theoretical switch to rosuvastatin/ezetimibe 40/10 mg/day. The percentage of patients who remained candidates for proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) was then calculated.

Results

Patients (n = 1694, mean age 50.8 ± 14.7 years) had LDL-C levels 242 ± 71 mg/dL (6.3 ± 1.8 mmol/L) at diagnosis. Most treated patients were receiving statins (97.5%) and about half were on additional ezetimibe (47.5%). Based on the 2019 ESC/EAS guidelines the percentage of patients achieving LDL-C goals was only 2.7%. Following theoretical up titration to rosuvastatin/ezetimibe 40/10 mg, LDL-C target achievement rate would increase to 5.9%. In this scenario, most patients (55.9%) would be eligible for PCSK9i treatment. Following theoretical administration of a PCSK9i, LDL-C target achievement rate would rise to 57.6%. However, 42.4% of patients would still be eligible for further LDL-C lowering treatment.

Conclusions

Most FH patients do not reach new LDL-C targets even if on maximum intensity statin/ezetimibe treatment. In this case, more than half of FH patients are candidates for PCSK9i therapy and a considerable proportion may still require additional LDL-C lowering.

Introduction

Familial hypercholesterolemia (FH) is the most common genetic metabolic disorder [1]. FH is attributed to gene mutations mainly of the low-density lipoprotein (LDL) receptor gene but also the apolipoprotein (apo) B-100 (APOB) gene, the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, and the LDLR adaptor protein 1 (LDLRAP1) genes [2], which result in increased levels of circulating LDL cholesterol (LDL-C). The ensuing hypercholesterolemia from birth leads to increased incidence of atherosclerotic cardiovascular disease (ASCVD) at an early age [3]. It is therefore of great importance to identify FH early in order to promptly initiate appropriate dietary and pharmacological interventions. The implementation of an aggressive hypolipidemic strategy is expected to reduce ASCVD risk in these patients [4], [5]. Indeed, data from large cohorts from the Netherlands [6], [7] and the United Kingdom [8], [9] have shown that statin treatment results in significant decrease of ASCVD risk (up to 76%).

Statins are the cornerstone of lipid lowering management and together with ezetimibe can greatly decrease LDL-C levels. Recent 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines recommend more aggressive LDL-C targets for patients with FH [<70 mg/dL (1.8 mmol/L) or <55 mg/dL (1.4 mmol/L) in the presence of established ASCVD or at least one major risk factor] [10]. However, in clinical practice LDL-C target achievement remains very low [11], [12]. This may be explained by statin underdosing, underprescription of ezetimibe and low adherence to therapy. Moreover, FH patients have remarkably high baseline LDL-C levels and therefore the combination of high intensity statin and ezetimibe may not be adequate.

As a result, many patients require additional LDL-C lowering therapies, such as bile acid sequestrants and PCSK9 inhibitors (PCSK9i). According to 2019 ESC/EAS guidelines PCSK9i are recommended in very-high-risk patients with FH (i.e., patients with ASCVD or with another major risk factor) if the treatment goal is not achieved on maximal tolerated statin plus ezetimibe as well as in FH patients who cannot tolerate statins. It is currently unknown how many FH patients are candidates for PCSK9i under 2019 ESC/EAS guidelines and in how many of them a fourth LDL-C lowering agent will be required. The primary endpoint of the present study was to explore the rate of LDL-C target achievement among adult FH patients. Secondary endpoint was to evaluate the impact of a theoretical treatment switch to rosuvastatin 40 mg/day plus ezetimibe 10 mg/day, as well as to assess the rate of eligibility for PCSK9i and the need for extra LDL-C lowering treatment.

Section snippets

Study design

The design and rationale of the HELLAS-FH registry have been previously described [13]. In brief, the registry is based on a network of sites that are distributed throughout Greece. Patients with FH are enrolled in an electronic database after signing informed consent form. For the diagnosis of FH in adults the Dutch Lipid Clinic Network (DLCN) criteria are used, which have been shown to have an 85% agreement rate with the genetic diagnosis [14], [15]. Patients with at least a possible

Results

A total of 1694 adult patients (860 male) were included in this analysis (mean age of 50.8 ± 14.7 years old) (Table 1). Of patients, 26.9% had hypertension, 7.1% type 2 diabetes and 25.6% were current smokers (Table 1). A total of 430 patients (25.4%) had established ASCVD (Table 1). Among patients, 61.4% (n = 1040) had a target LDL-C of ≤55 mg/dL and the rest (38.6%, n = 654) a target of ≤70 mg/dL.

The baseline and on-treatment lipid profile of patients is presented in Table 2. Patients at

Discussion

In the current study we showed an extremely low actual LDL-C goal attainment (2.7%) when 2019 ESC/EAS guidelines were applied to an FH cohort. Even after theoretical optimization of therapy to rosuvastatin/ezetimibe 40/10 mg daily, LDL-C target was achieved in only 5.9% of patients. As a result, a significant percentage of patients (55.9%) would be eligible for PCKS9i treatment. However, even after the theoretical addition of a PCKS9i in those eligible by the 2019 ESC/EAS guidelines, 42.4% of

Conclusions

In summary, most FH patients do not reach the latest 2019 ESC/EAS LDL-C targets. This highlights the necessity for more aggressive LDL-C lowering therapy with high intensity statin, ezetimibe and a PCSK9i. Even in that case, a considerable number of FH patients will need additional novel LDL-C therapies, such as bempedoic acid or ANGPTL3 inhibitors.

Author contributions

CVR and ENL contributed to analysis and interpretation of the data as well as the drafting of the manuscript. All authors were involved in critically revising the manuscript. All authors read and approved the final manuscript. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

Financial support

This study is funded by the Hellenic Atherosclerosis Society from grants provided by AMGEN HELLAS, SANOFI HELLAS, MSD HELLAS, AMRYT HELLAS, PHARMASERVE-LILLY HELLAS.

Declaration of Competing Interest

CVR, GS, AG, PA, VK, KT, ID, EK, DA, AA, and CA report no relationships that could be construed as a conflict of interest. IS has received research grants and honoraria from Amgen, Sanofi, MSD and Elpen. ES has participated in educational and advisory activities sponsored by AstraZeneca, Medtronic, MSD, Sanofi and Servier. LR has received honoraria for lectures, clinical trials and consultant fees from Amgen, MSD, MYLAN, Servier, AstraZeneca and Sanofi-Aventis. GK has given talks, attended

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