Elsevier

Progress in Cardiovascular Diseases

Volume 67, July–August 2021, Pages 65-74
Progress in Cardiovascular Diseases

How much should LDL cholesterol be lowered in secondary prevention? Clinical efficacy and safety in the era of PCSK9 inhibitors

https://doi.org/10.1016/j.pcad.2020.12.008Get rights and content

Abstract

There is a strong evidence that more marked lowering of low-density lipoprotein cholesterol (LDL-C) leads to progressively lower risk of cardiovascular disease (CVD) events. The evidence on validity of this hypothesis comes from epidemiological, genetic and clinical studies. The hypothesis “the lower the better” has been recently strongly supported by the results of secondary prevention trials with PCSK9 inhibitors. The combination of PCSK9 inhibitors and statins has resulted in achieving extremely low LDL-C levels with additional reduction of CVD events in secondary prevention. However, despite large clinical benefits, the safety of aggressive LDL-C lowering should be always taken into consideration, and there is still an ongoing discussion on whether very low LDL-C might result in some non-CVD adverse events. However, based on the available knowledge, so far the serious adverse events associated with achieving of very low LDL-C levels or intensive drug therapy have not been noted. These positive clinical effects were reflected in current ESC/EAS Guidelines (2019) for dyslipidaemia management. The experts strongly recommended the LDL-C lowering to levels that have been achieved in trials of PCSK9 inhibitors. In this state of the art review, we aimed to finally justify the critical need for LDL-C reduction to very low levels in secondary prevention patients in order to be as low as possible, as early as possible, and preferably lifelong.

Introduction

The question ‘how low should you go with low-density lipoprotein cholesterol (LDL-C)?’ is particularly pertinent in light of recent observations that further reduction of cardiovascular disease (CVD) events can be achieved in primary but, especially, in secondary prevention when very low LDL-C concentrations are achieved by adding proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to baseline lipid-lowering therapy.1., 2., 3. The approval of two PCSK9 inhibitors, evolocumab and alirocumab, expanded our therapeutic options but also raised some questions on safety concerns in relation to the low (<50 mg/dL, 1.3 mmol/L) and very low (<15–20 mg/dL, 0.4–0.5 mmol/L) concentrations of LDL-C achieved during therapy. To answer the question raised in the title of the present article, it is necessary to understand whether human organs and tissues require LDL-C, and if so, how much? The answers to these questions are informed by findings from population studies and the study of subjects with genetically determined low or very low LDL-C levels.4., 5., 6., 7. Equally important (to those with PCSK9 inihbitors) are the safety and efficacy findings of clinical trials using statins and other lipid-lowering drugs that achieved very low lipid levels, and the meta-analyses of these studies. This review summarises the relevant clinical evidence and explains how it has been used to inform the choice of LDL-C targets in clinical practice guidelines.

Section snippets

Cholesterol is essential for normal physiological functions

Recent advances in lipid-lowering therapy allow ever-lower LDL-C concentrations to be reached, especially when drugs are used in combinations. Consequently, the safety of extremely-low LDL-C levels has become a pertinent issue because cholesterol is known to be an essential component of cells. In general, cells have two sources of cholesterol: LDL and intrinsic synthesis. Recently, Masana et al. proposed an intriguing “zero LDL hypothesis” and performed a comprehensive review to evaluate it.8,9

Epidemiological studies

Mendelian Randomization (MR), prospective population and retrospective studies provided early evidence that total cholesterol (TC) and LDL-C levels are risk factors for CHD.25 The year 2019 marked the 70th anniversary of the initiation of the Framingham Heart Study (FHS).26 The association between TC and CHD was confirmed in the large prospective Multiple Risk Factor Intervention Trial (MRFIT) intrapopulation study in 361,622 middle-aged men.27 Of note, the MRFIT study did not identify any

Low LDL-C levels due to PCSK9 gene mutations – clinical cases and population studies

Case reports of individuals with loss-of-function mutations of the PCSK9 gene confirmed that the resultant low LDL-C levels do not lead to any adverse effects. These subjects are healthy, physically active and fertile, despite having circulating LDL-C concentrations as low as 0.4–0.8 mmol/L (14–29 mg/dL).6,7 In the Dallas Heart Study (12,887 individuals, including 3363 Afroamericans and 9524 Caucasians), the authors showed that PCSK9 gene mutations were associated with significantly lower LDL-C

Genetically determined low LDL-C levels – meta-analyses

MR studies have demonstrated that the risk of atherosclerotic CVD is lower in individuals with genetically determined lower LDL-C levels.29., 30., 31., 32.The same studies confirmed the rules that need to be especially met now based on numerous data available, that “the lower the better” cannot exist alone, it should be always accompanied with the “earlier the better” (on LDL-C goal of therapy), and “the longer the better”, preferably long-life.25,29., 30., 31., 32., 33.

Particularly valuable

Clinical trials as the basis for lower LDL-C targets in patients with acute coronary syndromes (ACS)

The history of how LDL-C targets in ACS have been incrementally reduced in response to the results of randomized clinical trials (RCTs) has been recently summarized by Quamar and Libby.36 Except for the ODYSSEY OUTCOMES study with alirocumab, no other clinical trial evaluated risk with the therapy targeted to achieve a specific LDL-C target.2 However, clinical trials evaluating statin monotherapy and combination therapy in the secondary prevention of CVD showed that the achievement of lower

Meta-analyses of clinical trials as the basis for lower LDL-C targets in secondary prevention

In addition to the results of the clinical trials described above, meta-analyses50., 51., 52. have contributed to the move towards lower LDL-C targets in secondary prevention. In 2014 Boekholdt et al. published a meta-analysis of 8 statin trials, with a total of 38,153 participants.50 This analysis aimed to evaluate the individual variation in LDL-C, non-HDL-C and ApoB level reduction, the proportion of patients who did not achieve LDL-C level <70 mg/dL (1.8 mmol/L) and, importantly, the

Findings of intravascular ultrasound imaging studies as justification for very low target LDL-C levels

Serial intravascular ultrasound of the coronary arteries enables evaluation of the relationship between concentrations of LDL-C achieved with lipid-lowering therapy and the volume of atheroma. Lower LDL-C levels are associated with greater plaque regression when patients are treated with intensive statin therapy or combination lipid-lowering therapy.58., 59., 60., 61., 62. In fact, the studies on statins already showed a significant effect of this therapy on atheroma plaque. Banach et al.in

Safety of using intensive lipid-lowering therapy to achieve low LDL-C levels

The most important issues related to the safety of intensive lipid-lowering therapy and low LDL-C include the effect on muscle symptoms, steroid hormone levels, neurocognitive function, and the occurrence of incident diabetes, malignancies and haemorrhagic stroke.65

In the PROVE IT TIMI 22 study, no significant differences were noted in the rates of myalgia, myositis, or CK elevation to ≥3 x upper reference limit between patients receiving intensive (atorvastatin 80 mg/d) and moderately

Conclusions and take-home message

Loss-of-function mutations of the PCSK9 gene lead to very-low LDL-C levels and are associated with a low CVD risk without adverse effects. Clinical trials of intensive statin therapy and of adding ezetimibe to statins have demonstrated that when lower LDL-C is reduced on therapy, this leads to reductions in the rate of CVD events. This observation in respect of LDL-C has been dubbed “the lower, the better”. Two monoclonal antibodies against PCSK9, evolocumab and alirocumab, when added to statin

Acknowledgment

Dr Cybulska has served as a consultant for Amgen and Sanofi-Aventis; Dr Kłosiewicz-Latoszek has served as a consultant for Amgen and Sanofi; Dr Penson owns four shares in AstraZeneca PLC and has received honoraria and/or travel reimbursement for events sponsored by AKCEA, Amgen, AMRYT, LinkMedical, Napp and Sanofi; Dr Nabavi has noting to disclose; Dr Lavie has served as a speaker and consultant for Amgen, Sanofi and Regeneron and in years past for most of the statin companies as well as on

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