Impact of statin therapy on LDL and non-HDL cholesterol levels in subjects with heterozygous familial hypercholesterolaemia

doi:10.1016/j.numecd.2021.01.014

Nutrition, Metabolism and Cardiovascular Diseases

Volume 31, Issue 5, 6 May 2021, Pages 1594-1603

https://doi.org/10.1016/j.numecd.2021.01.014 Get rights and content

Abstract

Background and aims

Cardiovascular risk in heterozygous familial hypercholesterolaemia (HeFH) is driven by LDL cholesterol levels. Since lipid response to statin therapy presents individual variation, this study aimed to compare mean LDL and non-HDL cholesterol reductions and their variability achieved with different types and doses of the most frequently prescribed statins.

Methods and results

Among primary hypercholesterolaemia cases on the Spanish Arteriosclerosis Society registry, 2894 with probable/definite HeFH and complete information on drug therapy and lipid profile were included.

LDL cholesterol reduction ranged from 30.2 ± 17.0% with simvastatin 10 mg to 48.2 ± 14.7% with rosuvastatin 40 mg. After the addition of ezetimibe, an additional 26, 24, 21 and 24% reduction in LDL cholesterol levels was obtained for rosuvastatin, 5, 10, 20 and 40 mg, respectively. Subjects with definite HeFH and a confirmed genetic mutation had a more discrete LDL cholesterol reduction compared to definite HeFH subjects with no genetic mutation. A suboptimal response (<15% or <30% reduction in LDL cholesterol levels, respectively with low-/moderate-intensity and high-intensity statin therapy) was observed in 13.5% and, respectively, 20.3% of the subjects.

Conclusion

According to the LDL cholesterol reduction in HeFH patients, the ranking for more to less potent statins was rosuvastatin, atorvastatin and simvastatin; however, at maximum dosage, atorvastatin and rosuvastatin were nearly equivalent. HeFH subjects with positive genetic diagnosis had a lower lipid-lowering response. Approximately 1 in 5 patients on high-intensity statin therapy presented a suboptimal response.

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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© 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Impact of statin therapy on LDL and non-HDL cholesterol levels in subjects with heterozygous familial hypercholesterolaemia

Abstract

Background and aims

Methods and results

Conclusion

Graphical abstract

Introduction

Section snippets

Study protocol

Results

Discussion

Conclusions

Authors' contributions

Acknowledgement of grant support

Declaration of competing interest

Acknowledgements

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