LDL cholesterol target achievement in heterozygous familial hypercholesterolemia patients according to 2019 ESC/EAS lipid guidelines: Implications for newer lipid-lowering treatments
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.
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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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2023, Journal of Clinical LipidologyCitation Excerpt :However, residual CV risk remains a major concern. Indeed, according to results from the HELLAS-FH registry, LDL-C target attainment using the 2019 ESC/EAS guidelines was 2.7%.5 When a theoretical optimization of therapy to rosuvastatin 40 mg (high-intensity statin) + ezetimibe 10 mg daily was applied, only 5.9% of patients achieved the LDL-C target.5