How low should we decrease lipid levels?

Introduction

Lipid disorders (dyslipidaemias) are one of the most widely spread metabolic disorders in the world. They do not cause immediate complications; the risk stems from the long-term effects of a high cholesterol level on the walls of the arteries, narrowing the arteries and restricting blood flow [1].

Exposure to elevated low-density lipoprotein cholesterol (LDL-C) causes the development of atherosclerotic plaques, which generates a broad spectrum of symptoms and disease syndromes. In this fashion, lipid disorders have a long-term impact on the health of the population, and the treatment of subsequent ischaemic complications represents a considerable burden on government budgets.

In the last decade, as a result of cooperation among geneticists, engineers, scientists and physicians, monoclonal antibodies - inhibitors of the proprotein convertase subtilisin/kexin type 9 (PCSK9) - have been developed, which block the PCSK9 enzyme responsible for the consolidated binding of the LDL-C molecule to its specific receptor (LDL-R) [2]. The overexpression of the PCSK9 enzyme (synthesised in the liver and excreted into the extracellular space) is associated with a lower LDL-R density and, consequently, with a higher level of LDL-C in the plasma.

With the new agents available, over the last decade, guidelines have pursued intensive lipid-lowering strategies, reducing the target cholesterol level to <55 mg/dL in patients at very high cardiovascular risk. While aggressive lipid-lowering strategies proved to reduce cardiovascular events, the long-term safety of this strategy, in particular the effect on stroke and cognition, remains unknown. Thus, despite the evolution of a dyslipidaemia management strategy, the questions remain essentially the same:

What is the optimal LDL-C level for patients at different cardiovascular risk?

By how much can we and should we lower the level of LDL-C?

What else should we take into consideration, apart from the patients’ risk profile and the LDL-C level goal?

The benefit of LDL-C lowering: the residual risk concept

Despite the achievement of systematically lowered LDL-C level goals, a significant residual risk of cardiovascular events persists in the general population. Atherosclerotic plaque build-up develops systematically over the years, all the more so when the level of circulating cholesterol is higher and the cumulative duration of exposure is greater. The most obvious example of this being patients burdened with familial hypercholesterolaemia [3]. Many complications of dyslipidaemia develop with age, but in familial hypercholesterolaemia the genetic predisposition prompts the cholesterol levels to be highly elevated from the beginning of life. This increases the risk of cardiovascular events in young people burdened with the disease, especially in the case of homozygous mutations, where heart attacks can affect even the paediatric population.

A similar phenomenon, albeit less dramatic, can be observed in the general population. A consensus statement from the European Atherosclerosis Society Consensus Panel, based on evaluation of the evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomisation studies, and randomised trials of LDL-C lowering therapies including more than 2 million participants with over 20 million person-years of follow-up, demonstrated a consistent dose-dependent association between the absolute magnitude of LDL-C exposure and the risk of atherosclerotic cardiovascular disease (ASCVD) [4]. This evidence emphasises the need to treat dyslipidaemia early, which may ultimately result in the need for less intensive therapy in the long term. Therefore, the absolute and extensive reduction of LDL-C level should reduce the risk of ASCVD events proportionally.

Another aspect of the residual risk issue is the patients who have achieved the goal of lipid-lowering therapy and still experience a prevalent rate of cardiovascular events. Traditionally, patients without cardiovascular risk factors were considered to be at low risk for atherosclerosis; however, they still experience cardiovascular events. In the study by Fernández-Friera et al [5], subclinical atherosclerosis was present in half of cardiovascular risk factor-free patients. An independent and direct link between LDL-C levels and atherosclerotic burden was present, supporting LDL-C lowering for primary prevention even in low-risk individuals. In addition to the risk originating from LDL-C levels alone, many pathways, including inflammatory, prothrombotic and metabolic, may contribute to recurrence of cardiovascular events [6]. For this reason, the early introduction of antidyslipidaemic drugs, which not only lower cholesterol but also exhibit pleiotropic effects beyond cholesterol lowering, can effectively prevent subsequent atherosclerotic events.

Numerous analyses have attempted to quantify the long-term benefit of LDL-C lowering and how this translates into a reduction of clinical endpoints. The meta-analysis conducted by the Cholesterol Treatment Trialists' (CTT) Collaboration gathered randomised data from 27 lipid-lowering clinical trials involving 174,149 participants, which, using individual patient data in those with a 5-year risk of major vascular events (MVE) lower than 10%, concluded that the analysed composite MVE (non-fatal myocardial infarction, coronary death, ischaemic stroke, or coronary revascularisation) were safely reduced with standard statin regimens, with each 1 mmol/l reduction of LDL-C resulting in a reduction of MVE by 22.5% [7].

New agents allowed lipid lowering even further than was possible before. The introduction of PCSK9 inhibitors tested in randomised controlled trials on a background of statin therapy allowed lowering LDL-C levels to 30 mg/dL and reduced the risk of cardiovascular events further [8]. While patients with ASCVD could benefit from lowering of LDL-C levels even below current targets, the latest long-term multicentre studies have not demonstrated the benefits of lipid-lowering treatment in reducing mortality, despite the inclusion of high or very high risk patients. In this regard, data from 34 trials (in which 136,299 patients received more intensive and 133,989 received less intensive LDL-C lowering) were analysed in terms of the impact of LDL-C on clinical events, and in order to assess which aspects of lipid-lowering therapy were the most important, i.e., whether it is the LDL-C goal or the value of LDL-C reduction, or if the outcome of the treatment depends on the initial level of LDL-C [9]. In the meta-analyses and meta-regressions performed, when more intensive was compared with less intensive LDL-C lowering, the higher the baseline LDL-C levels were, the greater was the reduction in the risk of major cardiovascular events (MACE).

Total mortality and cardiovascular mortality were also reduced in trials with higher baseline LDL-C levels; however, this association was only present when the baseline LDL-C level was above 100 mg/dL. Similar results were found in the ODYSSEY Outcomes trial, which included 18,924 patients with residual LDL-C levels ≥70 mg/dL who had an acute coronary syndrome (ACS) within the previous 12 months, randomised to either alirocumab or placebo [10]. In patients with a baseline LDL-C ≥100 mg/dL, both primary endpoint MACE and all individual endpoints were reduced over 2.8 years of follow-up.

The potential risk of LDL-C lowering: cognition and stroke risk

PCSK9 inhibitors shifted the limit of lowering LDL-C and raised a number of challenging questions. The first results of the ODYSSEY LONG TERM study, where alirocumab was administered on the background of maximally tolerated statin therapy, were surprising, with patients achieving and sustaining LDL-C levels as low as <15 mg/dL, without an increased risk of adverse events [11].

In the context of the results of recent trials and analyses, where the mortality rate was not statistically significantly reduced in the group of patients with baseline LDL-C level <100 mg/dL [9, 10], the balance between the cardioprotective benefits of potent LDL-C lowering and the controversies around extremely low LDL-C levels has been widely debated.

The new guidelines of the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) on lipid-lowering therapy recommend an even greater level of LDL-C reduction than previously [12]. Such a change could be dictated by the overall clinical and risk profile of the individual patient. In the JAMA analysis, patients with baseline LDL-C levels <100 mg/dL did not benefit from a more intensive lipid-lowering therapy in terms of overall mortality as well as cardiovascular mortality reduction. Notably, however, the frequency of revascularisation, myocardial infarction, cerebrovascular incidents and MACE was statistically significantly reduced in all baseline LDL-C subgroups, including in patients with low baseline LDL-C levels.

When establishing the individual lipid-lowering therapy it is necessary to reflect on the overall profile of the patient, including the potential severity of strokes, which many regard as being as important as death, considering the quality of life after such an incident and the resources required in providing care for disabled patients. The benefit of reducing LDL-C in terms of ischaemic events emerges from the stabilisation of the atherosclerotic plaque. A recently published study conducted in China, with 267,500 participants followed for 6 to 19 years (2,295,881 person-years), analysed the relationship between lipid profile and stroke [13]. The high levels of total cholesterol, triglycerides and LDL-C were positively associated with an increased risk of ischaemic stroke, while only a total cholesterol level of <120 mg/dL resulted in a higher risk of haemorrhagic stroke. The risks of both types of stroke might be increased with a high-density lipoprotein cholesterol (HDL-C) level lower than 50 mg/dL. On the other hand, in the SPARCL (Stroke Prevention With Aggressive Reductions in Cholesterol Levels) trial, which included patients who experienced a recent stoke/transient ischaemic attack, the prevalence of haemorrhagic stroke was significantly increased in patients randomised to atorvastatin 80 mg, compared with the placebo treatment group (post hoc analysis, hazard ratio [HR] 1.68, 95% confidence interval [CI]: 1.09 to 2.59), while the overall incidence of stroke and of cardiovascular events was significantly reduced. This information requires further research, considering the statistical heterogeneity and post hoc nature of the analysis; however, it signals the need for individual therapeutic decisions in patients at high risk of haemorrhagic stroke.

For many years it has been suspected that lowering cholesterol levels with lipid-lowering therapy may affect cognition, especially in patients in older age groups. The analyses of long-term statin therapy administration have found no association between statin therapy and neurocognitive adverse events; however, they were not sufficient to draw definitive conclusions [14, 15].

The PCSK9 antibodies, due to their hypolipidaemic effect, have the potential to stabilise the atherosclerotic plaque, which in turn reduces the occurrence of cardiovascular events. It has been theorised that too low cholesterol levels, however, may impair the synthesis of brain tissue elements, leading to impaired long-term cognition. A collective analysis of the ODYSSEY randomised controlled trials programme revealed that patients achieving LDL-C <25 versus ≥25 mg/dl experienced similar adverse event rates, including neurological and neurocognitive events, with only an increased rate of cataracts (2.6% vs 0.8%, respectively) [16]. It was not until the EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) trial, a substudy of the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibitors in Subjects With Elevated Risk) trial, that prospective data on cognition and intensive lipid-lowering became available [17,18]. A total of 1,204 out of 27,564 subjects enrolled in the main FOURIER trial were followed for 19 months and had their cognition assessed at entry and at the end of the study. There were no significant between-group differences for any of the memory tests assessed (executive function, working memory, episodic memory, or psychomotor speed), despite a 59% LDL-C level reduction with evolocumab compared with the mean baseline LDL-C level of 92 mg/dl in the placebo group. No associations between LDL-C levels and cognitive changes were found. While the results are reassuring, it is uncertain whether they can be extrapolated beyond a few years of follow-up and on the populations burdened with an increased risk for cognitive decline (age >75 years, very high atherosclerotic cardiovascular disease risk, history of ischaemic or haemorrhagic stroke) [19]. More long-term data are required to provide definite conclusions.

The guideline recommendation dynamics

The current ESC/EAS guidelines emphasise (I A recommendation) the need for lowering LDL-C with agents primarily upregulating the LDL-C receptor (statins, ezetimibe, and PCSK9 inhibitors), which in turn reduces the number of circulating LDL-C and apoB particles (Table 1) [12]. This strategy has been proven to reduce the risk of cardiovascular events in clinical trials and has the highest odds of fitting the patient’s lipid profile, as opposed to the uncertain effectiveness of therapies using different antidyslipidaemic mechanisms [20]. Notably, patients with low LDL-C levels and significantly increased triglyceride-rich VLDL-C remnant particles, may benefit most from therapy oriented to reduction of plasma triglycerides.

The optimal treatment should be tailored to the patient’s cardiovascular risk. New, more restrictive LDL-C treatment goals in patients at high risk (≥50% reduction from baseline and <1.8 mmol/L [<70 mg/dL]) and very high risk (≥50% reduction from baseline and <1.4 mmol/L [<55 mg/dL]) for ASCVD events prompted the need to emphasise a combination treatment with a maximally tolerated statin dose, first with ezetimibe and then with a PCSK9 inhibitor to achieve these targets (Table 2). Patients who have experienced an ACS are a very high risk group of particular interest, where a PCSK9 inhibitor should be introduced early after the event (if possible, during hospitalisation), or alternatively when the LDL-C goal is not achieved after 4 to 6 weeks despite maximally tolerated statin therapy and ezetimibe.

Table 1. Agents primarily lowering LDL-C.

HMG-CoA: β-hydroxy β-methylglutaryl-CoA; LDL-C: low-density lipoprotein cholesterol; PCSK9: proprotein convertase subtilisin/kexin type 9

Table 2. Author summary of the ESC/EAS 2019 guideline recommendations.

ASCVD: atherosclerotic cardiovascular disease; BP:  blood pressure; CKD: chronic kidney disease; CVD: cardiovascular disease; DM: diabetes mellitus; eGFR: estimated glomerular filtration rate; ESC/EAS: European Society of Cardiology/ European Atherosclerosis Society; FH: familial hypercholesterolaemia; LDL-C: low-density lipoprotein cholesterol; T1DM: type 1 diabetes mellitus; T2DM: type 2 diabetes mellitus; TC: total cholesterol

Conclusions

The current strong guideline recommendations prompt the initiation and maintenance of aggressive lipid lowering focused on LDL-C particles that is expected to translate into a maximum attainable reduction of ASCVD events, particularly in higher risk categories of patients, and increased long-term population health. Long-term efficacy and safety data are required to set the definitive therapeutic goals in the dynamically evolving field of dyslipidaemia.