Conversations on cholesterol: evaluating the role of LDL-cholesterol reduction in ASCVD

Br J Cardiol 2021;28(suppl 2):S7–S12doi:10.5837/bjc.2021.s07 Leave a comment
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Job code: 133819
Date of preparation: September 2021

There is now abundant evidence that apolipoprotein-B containing lipoproteins, low-density lipoprotein (LDL) in particular, are implicated in the causation of atherosclerosis, and are, therefore, prime targets in the prevention of atherosclerotic cardiovascular disease (ASCVD). The relationship between LDL and ASCVD risk appears continuous and graded, even down to very low levels of LDL cholesterol (LDL-C). Based on the ‘lower-is-better’ therapeutic paradigm, recent guidelines have set aggressive goals for LDL-C in very-high-risk patients. Using well-established and novel lipid-lowering therapies, we have the ability routinely to achieve the aggressive goals set out in the guidelines. However, to attain this outcome in the majority of patients, combination therapy would need to become the rule rather than the exception.

Introduction

Cardiovascular disease remains a major cause of morbidity and mortality in the UK even though mortality rates have declined significantly over the last 50 years.1 Improvements in the detection and treatment of people at elevated risk for atherosclerotic cardiovascular disease (ASCVD) have contributed to the decline, but findings from surveys of current practice indicate that much more could be done in both primary and secondary prevention settings to alleviate the disease burden.2 The following ‘conversations’ focus on recent developments in our understanding of the role of lipoproteins in ASCVD, and the potential of lipid-lowering interventions to generate even greater benefit than had been previously considered possible.

LDL is a causal risk factor for ASCVD and its effects are cumulative3

This statement summarises the conclusion of decades of research into the relationship of plasma lipoproteins to clinical cardiovascular disease and the underlying atherosclerotic processes that lead to deterioration of the structure and function of artery walls. The conversation revolves around questions such as ‘how certain are we that low-density lipoprotein (LDL) – and other apolipoprotein B (ApoB)-containing lipoproteins – are causal agents, and what is the nature of the relationship – is it ‘J-shaped’, like blood pressure and blood glucose, or uniformly linear?’ A recent review provides a detailed assessment of the role of LDL in the development of atherosclerosis.3 The robustness of the association is seen in evidence from multiple sources (figure 1). First, pathological investigations reveal the way in which LDL deposited in the artery wall promotes formation of early lesions (fatty streaks) and then complex plaques with lipid-filled necrotic cores that are prone to erosion or rupture, thereby precipitating a clinical event.4,5 Second, epidemiological studies show consistently that LDL-cholesterol (LDL-C), and the wider measure of non-high-density lipoprotein cholesterol (non-HDL-C), which includes LDL-C, cholesterol-enriched remnants derived from the lipolysis of triglyceride-rich lipoproteins, and lipoprotein(a) (Lp[a]),6 exhibit log-linear associations with ASCVD risk.6,7 Third, genomic analyses reveal that inherited variation in LDL (or ApoB) is linked to variation in ASCVD event rates.3,8 This is a critical observation since genetic associations are unlikely to be confounded by lifestyle factors.9 Fourth, lipid-lowering therapy trials (e.g. using statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) reveal a dose-response relationship – the greater the absolute reduction in LDL-C, the greater the decrease in relative risk,3,10,11 even down to very low LDL-C levels.11,12

Inclisiran supplement article 2: Figure 1. Low-density lipoprotein (LDL) – a causal, cumulative risk factor for atherosclerotic cardiovascular disease (ASCVD). Evidence sources underpin the association of apolipoprotein B-containing lipoproteins to ASCVD. The causal link between LDL and atherosclerosis has received support from all four domains. The relationship of remnant lipoproteins and lipoprotein(a) (Lp[a]) seen in epidemiology, genetics and experimental pathology has yet to be tested in outcome trials
Figure 1. Low-density lipoprotein (LDL) – a causal, cumulative risk factor for atherosclerotic cardiovascular disease (ASCVD). Evidence sources underpin the association of apolipoprotein B-containing lipoproteins to ASCVD. The causal link between LDL and atherosclerosis has received support from all four domains. The relationship of remnant lipoproteins and lipoprotein(a) (Lp[a]) seen in epidemiology, genetics and experimental pathology has yet to be tested in outcome trials3,36,37

It is now appreciated that the deleterious effects of LDL on the artery wall are cumulative.3,5,8,11 Atherosclerosis develops over decades and longitudinal studies in populations reveal that the impact of LDL can best be explained by cumulative exposure, that is ‘LDL-C level × years of exposure’.3,8,13 This pathogenic feature helps explain why people with familial hypercholesterolaemia (FH) who are born with high LDL (due to genetic defects mainly in the LDL-receptor) are at risk of developing early onset atherosclerosis and coronary heart disease.13 Since women have lower LDL-C than men until the menopause, the cumulative exposure paradigm also accounts for the well-known 10-year difference between the sexes in the appearance of clinical manifestations of cardiovascular disease.14 Genetic studies have also been very revealing. Inheritance of a loss-of-function (LOF) variant in the PCSK9 gene leads to increased LDL-receptor activity, lifelong lower LDL levels and delayed appearance of ASCVD.3,15,16

All cells in the body require cholesterol to maintain their functionality. They acquire it from the blood by taking up LDL or synthesise it for themselves (from acetate).17,18 The availability of the latter option seems to account for the observation that LDL can be very low or virtually absent from the bloodstream due to pharmacologic intervention or inherited traits and yet, according to current evidence, there is not an associated increased prevalence of adverse events.11,19 There have been lingering questions about the safety of lowering LDL intensively, but outcome trials, with PCSK9 inhibitors (evolocumab and alirocumab) in particular, show no evidence of excess adverse effects.12,20 Specific attention was paid to key serious adverse events including neurocognitive function, haemorrhagic stroke, and cancer and no increase was seen in these outcomes when LDL-C was reduced to very low levels (<1.3 and even <0.5 mmol/L).12 On the basis of this evidence, the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) 2019 guidelines conclude that “no level of LDL-C below which benefit ceases or harm occurs has been defined”.11 The association between LDL and ASCVD is continuous and graded, and there is no theoretical reason not to reduce LDL-C profoundly.11,21

LDL-lowering agents used in combination give additional risk reduction

With the ‘lower-is-better’ treatment paradigm supported by a raft of scientific evidence, the next conversation focuses on how we achieve substantial reductions in LDL-C. A number of effective, and generally well-tolerated LDL-lowering agents have been developed, namely statins, ezetimibe, PCSK9 inhibitors (alirocumab and evolocumab) and, most recently, bempedoic acid and inclisiran.11,22,23 As shown in figure 2 these agents, while acting on different targets, share a final common pathway by which they lower LDL – that is by increasing the activity of LDL-receptors in tissues, mainly the liver. Statins, by inhibiting a key enzyme in the cholesterol synthesis sequence, lower cell cholesterol levels and trigger production of more LDL-receptors, which move to the cell surface and mediate uptake of the lipoprotein from the circulation (figure 2).11 Bempedoic acid works in a similar way by inhibiting an earlier enzyme in the cholesterol synthesis pathway.23 Ezetimibe acts in the intestine to decrease uptake of luminal cholesterol and reduce the amount of this lipid delivered to the liver (in chylomicrons).11 PCSK9 is a protein that alters the metabolic fate of LDL-receptors in cells. When it is present, it binds to the LDL-receptor and promotes its degradation. The resultant drop in receptor-mediated LDL uptake leads to increased LDL-C levels.11 A number of drugs have been developed that act on the PCSK9 pathway to increase LDL-receptor activity and lower LDL-C, including monoclonal antibody-based PCSK9 inhibitors alirocumab and evolocumab,11 and the small-interfering (si) RNA product inclisiran. Inclisiran is reviewed in detail in the next paper in this supplement (pages S13–S18).11,22

Inclisiran supplement article 2: Figure 2. Mode of action of LDL-lowering agents
Figure 2. Mode of action of LDL-lowering agents4

The relative ability of these drug classes to reduce LDL-C is shown in figure 3. Statins are accepted universally as first-line therapy. These drugs have been tested extensively in clinical trials and been found to be generally well tolerated and efficacious.10,11 Long-term follow-up of landmark trials (notably conducted in the UK using registry data) showed that the benefits of statin therapy persisted over the long term and no late-appearing adverse effects were detected.24 However, it is now recognised that risk of developing type 2 diabetes is increased modestly by statins, but in an overall risk–benefit assessment, this is more than offset by the decrease in ASCVD risk.11 A ‘moderate-intensity’ regimen lowers LDL-C by 30–50% while higher doses or more potent alternatives yield >50% reductions.11 Up-titrating the dose of a statin leads to about a 6% further drop in LDL-C; a surprising but consistent finding that we now understand better since statins have been found to increase PCSK9 production.25,26

Inclisiran supplement article 2: Figure 3. Typical percentage low-density lipoprotein cholesterol (LDL-C) reductions using major classes of drugs
Figure 3. Typical percentage low-density lipoprotein cholesterol (LDL-C) reductions using major classes of drugs

Second-line therapies, which include the cholesterol absorption inhibitor ezetimibe, the PCSK9 inhibitors alirocumab and evolocumab, and bempedoic acid, have enabled further reductions in LDL-C through combination with statins and/or other lipid-lowering therapies. Ezetimibe has been shown to reduce LDL-C by an average 18.5%,11,27 and by an additional 21–27% when added to ongoing statin therapy.11 The PCSK9 inhibitors show an average reduction in LDL-C of 60% depending on dose, with efficacy appearing largely independent of any background therapy. In combination with high-intensity or maximally tolerated statins, alirocumab and evolocumab reduce LDL-C by 46–73% more than placebo.11 Bempedoic acid has been shown to reduce LDL-C by 18% when given in combination with a statin or other lipid-lowering therapies.23

Two features of the action of these drugs are worthy of note in the context of this discussion. First, they all increase clearance of LDL particles from the bloodstream.3,11 The alternative of inhibiting synthesis and assembly of ApoB-containing lipoproteins (very-low density lipoprotein [VLDL], the LDL precursor) causes problems linked to fat accumulation in the liver.11 Second, the LDL lowering seen when one drug is added to another is additive. That is, the percentage LDL-C decrease on ezetimibe or a PCSK9 inhibitor is similar whether the agent is given on top of statin therapy or alone.11,28,29 In retrospect, this is a remarkable finding given that all agents are impacting on the same metabolic pathway.

Since there is robust evidence that the association of LDL-C with ASCVD is continuous across the population concentration range down to low levels, then the additive action of LDL-lowering agents has the potential to lead to further benefit in terms of risk reduction, and this has been borne out in trials of combination therapy (figure 4). The earliest statin–placebo outcome trials showed the remarkable effectiveness of these drugs in reducing risk of myocardial infarction (MI), stroke, and other manifestations of ASCVD. This was followed by the demonstration that compared with less intensive regimens, more intensive regimens led to a further increment in benefit.30 It was not until 2015 that successful combination therapy trials began to report their findings.

Inclisiran supplement article 2: Figure 4. Clinical outcome trials of LDL-lowering agents and years when reported. There are as yet no outcome trial data reported for inclisiran or bempedoic acid
Figure 4. Clinical outcome trials of LDL-lowering agents and years when reported. There are as yet no outcome trial data reported for inclisiran or bempedoic acid

IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) demonstrated a small but significant risk reduction on ezetimibe plus statin versus statin alone.31 The average LDL-C levels in the two arms during the study were 1.4 mmol/L versus 1.8 mmol/L, respectively. The PCSK9 inhibitor trials, FOURIER and ODYSSEY Outcomes, evaluated more profound LDL-C reductions to average levels of 0.8 mmol/L and 1.2 mmol/L, respectively (at 12 months from a baseline of 2.4 mmol/L). These reductions corresponded with a 15% decrease in relative risk of the primary end point of a composite of cardiovascular outcomes.32,33 On the basis of these findings, it has been concluded that intensive LDL-lowering is an appropriate therapeutic strategy,11 and meta-regression analysis has revealed a seemingly universal rule that a 1.0 mmol/L drop in LDL-C is associated with a 22% decrease in relative risk of major vascular events, and this relationship appears to hold across the entire concentration range.11,30,34

The effect of bempedoic acid and also of inclisiran on cardiovascular morbidity and mortality has not yet been determined.

A tailored, needs-based approach to intensive LDL-lowering is now achievable

The evidence-base described above supports the paradigm that ‘lower is better’ and the question arises as to how to apply this scientific framework to clinical practice. The conversation here centres on the setting of therapeutic goals and how these can be implemented taking into account individual patient needs. 2019 saw the publication of the updated ESC/EAS guidelines, which included aggressive goals for the management of lipids in ASCVD prevention.11 Table 1 sets out the risk categories and associated recommended goals for LDL-C. The most noteworthy changes, relative to earlier versions, are the adoption of a goal for very high-risk patients of <1.4 mmol/L (reduced from <1.8 mmol/L in the 2016 EAS/ESC guidelines).35 In light of the findings from outcome trials, this alteration was assigned a Class I evidence rating. A further innovation was the very aggressive goal of <1.0 mmol/L for patients with established cardiovascular disease who suffered repeat ASCVD events within a two-year period.11 While this recommendation was not considered as strong as the others, it was a recognition of the findings in PCSK9 inhibitor trials.32,33

Table 1. European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guideline goals for lipid lowering therapy.11 Green background denotes Class I and yellow Class 2 recommendations

LDL-C (mmol/L) Non-HDL-C (mmol/L) ApoB (mg/dL)
Low-risk primary prevention <3.0
Moderate-risk primary prevention (7.5%–20% CHD risk, SCORE <5%) <2.6 <3.4 <100
High-risk primary prevention (risk enhancers, SCORE 5–10%) <1.8 <2.6 <85
Very-high-risk primary prevention (FH, SCORE >10%) <1.4 <2.2 <65
Very-high-risk secondary prevention ASCVD <1.4 <2.2 <65
Secondary prevention ASCVD (aggressive disease) <1.0
Individuals at very high risk should also aim for a LDL-C reduction of >50% from baseline
Adapted from data derived in Mach et al.11

Cholesterol associated with atherogenic ApoB-containing lipoproteins is found in VLDL and its remnants, intermediate-density lipoprotein (IDL), LDL, Lp(a), and to a variable extent in chylomicrons and their remnants (after a meal).11,36,37 The amount of Lp(a) is also highly variable and determined mainly by genetic factors.37 Non-HDL-C and ApoB provide measures of the total abundance of all atherogenic species; LDL-C is by far the most numerous of the ApoB-containing lipoproteins.11,36 Secondary goals for non-HDL-C and ApoB were given to aid in treating individuals with high levels of remnant lipoproteins or Lp(a). Patients at very high risk with elevated non-HDL-C (e.g. those with hypertriglyceridaemia) might merit more aggressive therapy even if LDL-C is close to, or at, goal.11 Extremely elevated Lp(a) is twice as common as heterozygous familial hypercholesterolaemia (FH) and can be a concern. This lipoprotein is not lowered by statins but does respond to an extent to PCSK9 inhibition.11

Meeting these updated guideline recommendations requires an updated therapeutic approach. According to surveys of lipid levels in treated ASCVD patients, statin use alone, even at high doses, will be insufficient to reach these more ambitious goals.2 The recent DA VINCI study (EU-Wide Cross-Sectional Observational Study of Lipid-Modifying Therapy Use in Secondary and Primary Care)2 reported that less than half of secondary prevention patients attained the previous 2016 ESC/EAS goal of <1.8 mmol/L with statin monotherapy.35 This may be in part attributed to intolerance to statins due to side effects such as myalgia,11 and also to non-adherence.38 In order to meet the goals in table 1, it will be necessary for combination therapy to become the rule rather than the exception for very-high-risk patients. For some, the use of statin plus ezetimibe (generic, oral therapies) will suffice; in IMPROVE-IT the mean LDL-C achieved in the combination therapy arm (simvastatin/ezetimibe) in very-high-risk post-acute coronary syndrome (ACS) participants was 1.4 mmol/L compared with 1.8 mmol/L in the simvastatin monotherapy arm.31

Both the recent European and American College of Cardiology (ACC)/American Heart Association (AHA) updated guidelines recommend using PCSK9 inhibitors to address the unmet need when patients are too far from goal for ezetimibe to be adequate.11,39 Given the cost-benefit considerations associated with prescribing PCSK9 inhibitors, guidelines promote the adoption of a ‘highest risk–highest benefit’ approach.11 This is based on the recognition that those with the highest LDL-C on statin therapy will have the largest absolute LDL-C decrease and, hence, the greatest relative-risk reduction when given a PCSK9 inhibitor (figure 3).40 If they also have a high ongoing risk of a future ASCVD event then the absolute risk reduction becomes substantial (relative reduction × ongoing risk level) and the number-needed-to-treat (NNT – the reciprocal of the absolute risk reduction over a given period) is small.

In an analysis of subjects with significant ASCVD in FOURIER,41 it can be seen that typical groups of patients at highest risk – for example, those with a more recent MI (<2 years), multiple prior MIs or residual multi-vessel coronary disease – had greater relative (and absolute) risk reductions for the primary end point on combined therapy and a NNT over three years of <30, demonstrating the value of further LDL-lowering. Stratifying a clinic or practice population on the basis of ASCVD history, perceived ongoing risk and on-statin LDL-C (or non-HDL-C) will allow the identification of those who will benefit most from combination lipid-lowering treatment. As a benchmark, in FOURIER approximately half of the entire cohort had ‘highest-risk’ status.41,42 With a range of therapies now available, we have the means to tailor treatment and seek to achieve whatever goal is judged most appropriate for the level of risk.

Conclusion

The relationship of LDL to ASCVD is now well understood and provides a sound basis on which to establish therapeutic strategies. Intensive LDL-lowering is achievable and, tailored to the needs of the highest risk patients, delivers substantial clinical benefit.

Key messages

  • The causal, linear relationship of low-density lipoprotein (LDL) to atherosclerotic cardiovascular disease (ASCVD) underpins current therapeutic strategies
  • Combination LDL lowering is generally well-tolerated and efficacious, and provides additional, substantial benefit beyond that achieved with statin monotherapy
  • Stratification of patients with established ASCVD on the basis of risk identifies those who benefit most from combination lipid-lowering treatment

Conflicts of interest

CJP has received honoraria/grants from Amgen, Daiichi-Sankyo, Dalcor, and MSD.

Chris J Packard
Honorary Senior Research Fellow

Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow, G12 8TA

(chris.j.packard@gmail.com)

Articles in this supplement

Cardiovascular disease: the state of the nation, and the NHS Long Term Plan

New opportunity for cholesterol lowering: inclisiran

Inclisiran: testing a population health management methodology to implement a novel lipid treatment

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