Impact of statin therapy on LDL and non-HDL cholesterol levels in subjects with heterozygous familial hypercholesterolaemia
Graphical abstract
Introduction
Heterozygous familial hypercholesterolaemia (HeFH), the most frequent monogenic disorder of human metabolism caused by mutations in the genes encoding for the low-density lipoprotein (LDL) receptor [1], apolipoprotein (Apo) B [2], proprotein convertase subtilisin/kexin-type 9 (PCSK9) [3] or apo E [4], entails high LDL cholesterol concentrations. Natural history studies in HeFH revealed that approximately 50% and 30% of men and women, respectively, would develop coronary heart disease by the age of 50 [[5], [6], [7]]. The introduction and widespread use of statins in recent years has markedly improved the prognosis for these patients [[8], [9], [10], [11]]. However, the sad reality is that HeFH patients are undertreated and the achievement rate of therapeutic goals is unacceptably low [[12], [13], [14], [15]]. Therefore, the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society [16] (EAS) guidelines for the management of dyslipidaemias advocate starting cholesterol-lowering treatment with high-intensity statins, in most cases combined with ezetimibe, as soon as possible after HeFH diagnosis and recommend a more aggressive LDL cholesterol therapeutic target in this specific population.
It has been assumed that the relative reduction in LDL cholesterol with statins in HeFH patients is roughly the same as in the general population regardless of the genetic defect [17,18], although absolute reductions often exceed those reported in the general population owing to higher baseline LDL cholesterol in HeFH patients. Similarly, the established dose-dependent LDL cholesterol reduction with statins and their different potency in terms of LDL-lowering effect also applies to HeFH. Furthermore, the response to the same statin dose revealed a considerable individual variation in patients without HeFH [19,20] and although the exact mechanism remains a matter of debate, high LDL cholesterol levels appear to play a role in this variability [21].
Cardiovascular risk in HeFH is largely driven by LDL cholesterol levels, with the efficacy of lipid-lowering therapy being based on mean LDL cholesterol reductions among randomised trials and among statins performing head-to-head. The present study aimed to compare mean LDL and non-high-density lipoprotein (HDL) cholesterol reductions and their variability achieved with different doses of the 3 most frequently prescribed statins in monotherapy or combined with ezetimibe, using individual data of clinically-defined HeFH subjects of the Spanish Atherosclerosis Society (SEA) Dyslipidaemia Registry. The percentage changes in LDL and non-HDL cholesterol with statins alone in HeFH subjects with a confirmed genetic mutation together with factors associated with a suboptimal response in LDL cholesterol levels were also evaluated.
Section snippets
Study protocol
The SEA Dyslipidaemia Registry was created on 2013 as an active on-line registry in which 65 certified lipid clinics across Spain report cases of various types of primary hyperlipidaemias [22]. Anonymous clinical data collection in this registry was approved by a central ethics committee (Comité Ético de Investigación Clínica de Aragón, Zaragoza, Spain) in accordance with the 1975 Declaration of Helsinki and participants gave their written informed consent. Minimum data for the inclusion of
Results
Of the 2894 included patients, 540 presented probable and 2354 definite HeFH (Fig. 1). The main clinical characteristics of the patients together with family and personal history and baseline lipid profile are described in Table 1: 1907 (65.9%) presented definite HeFH with a confirmed genetic mutation, 447 (15.4%) definite HeFH with no genetic mutation and 540 (18.7%) probable HeFH. Mean follow-up time of the subjects was 5.2 ± 3.1 years.
Discussion
The present study evaluated LDL and non-HDL reductions in HeFH patients with different types and doses of statins alone or combined with ezetimibe in a real clinical setting. Rosuvastatin 40 mg and atorvastatin 80 mg in monotherapy were superior to the other statins type and doses regarding LDL and non-HDL cholesterol level improvement. As to combined treatment, rosuvastatin 40 mg was superior to the other types of statin regarding LDL and non-HDL cholesterol normalisation, and was also
Conclusions
In our real clinical setting, in HeFH patients, rosuvastatin mg to mg was more potent than atorvastatin and this in turn more than simvastatin. However, the maximum doses of atorvastatin and rosuvastatin, 80 and 40 mg, respectively, were nearly equivalent regarding lipid profile normalisation. HeFH subjects with a confirmed genetic mutation appeared to have a slightly lower lipid-lowering response than other subjects. This suggests that the LDL cholesterol-lowering effect of statins is lesser
Authors' contributions
All authors contributed to the study conception and design. Material preparation and data collection were performed by all authors. Data analysis was performed, and the first draft of the manuscript was written by EC, DB and J.P–B, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Acknowledgement of grant support
This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.
Declaration of competing interest
Dr. Climent has nothing to disclose. Dr. Marco-Benedí has nothing to disclose. Dr. Benaiges has nothing to disclose. Dr. Pintó reports personal consulting fees from Amgen and Sanofy, and payment for lectures from Astra-Zeneca, Esteve, Ferrer and Mylan. Dr. Manuel Suárez Tembra payment for lectures from Mylan and Sanofi, outside the submitted work. Dr. Plana has nothing to disclose. Dr. Lafuente reports payment for lectures from Amgen, Ferrer, Mylan and Sanofi, outside the submitted work. Dr.
Acknowledgements
We thank the personnel of Spanish Lipid Clinics for inclusion of cases in the Dyslipidaemia Registry of the Spanish Arteriosclerosis Society, and Miss Christine O'Hara for review of the English version of the manuscript. Sanofi provided a research grant to support the Dyslipemia Registry of the Spanish Atherosclerosis Society, but had no role in the study design, data collection, analysis, and interpretation, report writing, or decision to submit for publication.
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