Lancet- Invited Review

Pharmacological Lipid Modification Therapies for the Prevention of Ischaemic Heart Disease-

Current and Future Options

Professor Kausik K Ray FRCP1, Pablo Corral MD2, Enrique Morales PhD3, Professor Stephen J

Nicholls PhD4

All authors contributed equally to this manuscript

1Imperial Centre for Cardiovascular Disease Prevention, School of Public Health, Imperial College

London, London UK,

2 Pharmacology Department, School of Medicine, FASTA University, Mar del Plata, Argentina.

3 Cardiometabolic Research Center, MAC Hospital, Aguascalientes, México

4 Monash Cardiovascular Research Centre, Monash University, Melbourne, Australia

Correspondence to

Prof Kausik K Ray

Imperial Centre for Cardiovascular Disease Prevention, School of Public Health, Imperial College London, UK

k.ray@imperial.ac.uk

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Summary

Atherosclerosis and its clinical manifestations as ischaemic heart disease (IHD) remains a

significant health burden. As many factors contribute to IHD, a multifactorial approach to

prevention is recommended starting with lifestyle advice, smoking cessation and control

of known cardiovascular risk factors such as blood pressure and lipids. Within the lipid

profile the principle target is lowering low density lipoprotein cholesterol (LDL-C) first with

lifestyle then with pharmacological therapy. Statins are the first line pharmacological

treatment recommended. Some individuals may require further LDL-C lowering or are

unable to tolerate statins. Additional therapies ranging from small molecules taken orally,

to injectable therapies targeting different pathways in cholesterol metabolism are now

available. These include ezetimibe targeting the NCP1L1 receptor and monoclonal

antibodies targeting PCSK9. Phase three trials have also been completed for bempedoic

acid (targeting ATP Citrate Lyase) and inclisiran (an interference RNA based therapeutic)

targeting hepatic PCSK9 synthesis. Beyond LDL-C lowering Mendelian randomization

studies support a causal role for lipoprotein(a) and triglycerides. In this narrative review

we appraise currently available and emerging therapies for lowering LDL-C, lipoprotein(a)

and triglycerides for IHD prevention.

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Introduction

Prevention of ischaemic heart disease (IHD) requires a multifactorial approach starting

with a healthy lifestyle and control of risk factors such as blood pressure and lipids.

Despite early promise from therapies such as fibrates and niacin, 1 2 3 lipid modification

therapy for the prevention of IHD came into their own with the development of statins

and the first large cardiovascular outcome trials. 4 5 These trials also stimulated the search

for alternative pathways by which LDL-C could be lowered. Rapid progress in genomics

and genetic epidemiology have led to the identification of novel drug targets for the

regulation of LDL-C. The same approaches have identified lipoprotein(a) (Lp(a)) and

pathways related to triglyceride metabolism as promising lipid targets for the prevention

of IHD. Whilst small molecules administered daily targeting key steps in lipid metabolism

have been the mainstay of therapy, advances in drug development now offer injectable

biologics and RNA based therapeutics with the possibility of less frequent dosing regimens

to small molecules. In this review we discuss: the relevance of LDL-C, Lp(a), triglycerides

(TG) and high density lipoprotein cholesterol (HDL-C) to IHD and appraise the pathways by

which they may be modulated by current and future therapies (Figure 1 and Table 1). Each

section focuses on a specific lipid, describing the mechanisms of action of current and

future therapies against the specific target, the clinical research evidence to date and their

position in clinical guidelines.

LDL-C lowering

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Basic science research, epidemiological studies including genetic studies and randomized

clinical trials (RCTs) support a causal and cumulative role for low density lipoprotein

cholesterol (LDL-C) and risk of ischaemic heart disease (IHD).6 In this section we discuss

therapies shown to reduce both LDL-C and IHD risk (statins, ezetimibe and PCSK9-mAbs)

and other therapies (bile acid sequestrants and niacin) that lower LDL-C but with less

contemporaneous evidence for prevention of IHD. Finally, we review cholesterol ester

transfer protein (CETP) inhibitors originally developed for HDL-C raising but now viewed as

potential LDL-C lowering therapies as well as bempedoic acid and inclisiran which are first

in class small molecules and siRNA based therapies respectively, as well as LDL-C lowering

therapies specific to Homozygous FH (lomitapide and mipomersen).

Statins

Mechanism of action. Statins are small molecules that compete selectively with the enzyme

HMGCoAR in the metabolic pathway for cholesterol synthesis. This results in a decrease in

intracellular cholesterol concentration with subsequent activation of the transcription of

steroid regulatory binding protein type 2 (SREBP-2), which promotes genes coding for the

synthesis of the LDL receptor (LDLR). The latter increases the catabolic rate of

apolipoprotein B100 (apo-B) containing lipoproteins thus lowering LDL-C, non-HDL-C and

apo B. 7 8

Clinical research evidence. Between 1976-1986, the development of statins centred around

the treatment of hypercholesterolemia "per-se", culminating in a report in 1981

demonstrating for the first time that it was possible to reduce LDL-C by as much as 29% in

subjects with heterozygous familial hypercholesterolemia (HeFH).9 The 4S trial in 1994 was

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the first RCT that ushered in the statin era with evidence that individuals with pre-existing

IHD, and high LDL-C (mean 4.88 mmol/L), benefited from LDL-C reduction resulting in lower

rates of cardiovascular events and mortality. 4 These findings were extended through a

serious of RCTs to populations with even lower cholesterol levels among those with

(secondary prevention) and without prior vascular disease (primary prevention). Meta-

analyses of these trials covering over 25 years of research are summarized in Table 2. 10-13

With the exception of subjects with non-ischemic heart failure or renal failure in

replacement phase, each unit change in LDL-C produces a similar decrease in the relative

risk of a major cardiovascular event, independently of the overall baseline risk, of gender,

age and pre-treatment lipid levels. The cardiovascular benefits are not offset by an excess

in the incidence of cancer or non-cardiovascular death or any major life-threatening

adverse event. The absolute risk reduction also increases directly with the overall baseline

risk and with the absolute reduction in LDL-C from therapy. Thus numbers needed to treat

(NNT) to prevent one event are lowest for those with higher pre-treatment cardiovascular

risk, and higher baseline LDL-C levels and for those achieving greater LDL-C reductions.

Guideline recommendations. Statins are recommended as first-line pharmacological therapy

for the reduction of LDL-C and for the prevention of atherosclerotic cardiovascular (ASCVD)

risk. Global guidelines also recommend a risk-based approach whereby the aim of LDL-C

lowering is to “titrate” LDL-C reductions and LDL-C levels to match the predicted absolute

pre-treatment risk. 14 15

Ezetimibe

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Mechanism of action. Ezetimibe is a small molecule which inhibits the selective absorption of

cholesterol through the Niemann-Pick C1 Like 1 receptor (NCP1L1) in the intestine; this

results in an indirect increase in the synthesis of the LDLR. 16 As monotherapy or when added

to statins ezetimibe reduces LDL-C by approximately 20-25%.17

Clinical research evidence. The SHARP trial 18 in a chronic kidney disease population

comparing statin plus ezetimibe versus placebo demonstrated that the magnitude of relative

reduction in clinical events was consistent with the absolute reduction in clinical events

predicted from the cholesterol treatment trialist (CTT) meta-analysis. This did not prove

however that ezetimibe was safe and effective and it was the IMPROVE-IT trial 19 comparing

statin plus ezetimibe versus statin alone, that demonstrated that LDL-C lowering with

ezetimibe reduced cardiovascular events (Table 2). Ezetimibe was safe and whilst the

magnitude of the relative benefit appeared small for a primary endpoint it needs to be

analysed in the context of the CTT findings. The absolute difference of 0.43 mmol/L lowering

conferred a relative treatment benefit 7.2% on the risk of major cardiovascular events (CTT

principal endpoint), which is consistent with the proportional reduction in risk of around 21

% expected from a 1mmol/L absolute LDL-C reduction. The absolute lowering of risk in

IMPROVE IT trial was 2.0% overall, however the benefit of even modest reductions in LDL-C

among high risk subgroups was demonstrated by the observation that among those with

diabetes,20 and prior CABG,21 for example the same difference in LDL-C conferred a greater

absolute benefit of the order of 5.5% to 8.8%. Finally, whilst the PROVE IT trial demonstrated

for the first time that in setting of post-acute coronary syndromes (ACS), lowering LDL-C

levels to approximately 1.8mmol/L conferred a lower risk versus LDL-C levels of

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approximately 2.5 mmol/L,22 IMPROVE-IT 19 extended the lower limit of benefit from a LDL-C

of 1.8mmol/L to 1.4mmol/L in the post-ACS setting. Fixed dose combinations with statins are

available offering a lower pill burden for those needing combination therapy.

Guideline recommendations. Ezetimibe is the second line pharmacological agent

recommended by most clinical guidelines for the reduction of LDL-C levels and prevention of

ASCVD, when maximal tolerated doses of statin alone produce insufficient reductions in LDL-

C for the level of risk in the individual. 14 15

Monoclonal antibodies to PCSK9

Mechanism of action. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the

LDLR and prevents its recycling to the cell surface, resulting in fewer LDLRs. All lipid lowering

therapies result in a reciprocal increase in hepatic PCSK9 production which limits their

efficacy. Monoclonal antibodies (mAbs) directed against PCSK9 recognize the catalytic

domain of PCSK9 and prevent its binding to the LDLR; through this mechanism the PCSK9-

mAbs directly increase the lifecycle of the LDLR. 23

Clinical research evidence. Among individuals with non-familial hypercholesterolemia and

heterozygous hypercholesterolemia, when added to statins, ezetimibe or as monotherapy

the PCSK9-mAbs reduces LDL-C by between 50-60%, and non-HDL-C and apoB by 40%-

50%.24,25 Reducing LDL-C through this mechanism when added to statins and against a

background of contemporary standards of care has been shown to reduce cardiovascular

events with fixed doses of evolocumab in a population with stable cardiovascular disease 24

and with a variable dosing regimen alirocumab to target a specific LDL-C range conducted in

the setting of a recent ACS (Table 2). 25 Except for a small but significant excess of injection

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site reactions observed for evolocumab and alirocumab (0.5% and 1.7% respectively) versus

placebo, no significant difference was reported in adverse events.

Whilst at first the benefits achieved from a further a 50-60% reduction in LDL-C

from the two PCSK9-mAbs trials may seem modest, these results need to be reconciled with

the fact that the proportional reduction in risk is related to the absolute LDL-C difference and

the relative benefits in the first year of treatment are approximately half per 1mmol/L

reduction compared to latter years. Taking these differences into account, the relative

reductions observed overall in these trials correspond well to the predicted benefits from

CTT standardised per 1mmol/L lowering of LDL-C and duration of treatment.26 Further

analyses have helped to identify clinical characteristics associated with greater absolute risk

who derive greater absolute benefits from PCSK9-mAbs, including baseline LDL-C

>2.5mmol/L,25 diabetes,27,28 peripheral vascular disease,29 two or more myocardial

infarctions, multi-vessel disease and recent myocardial infarction.30 In the FOURIER trial

these profiles of very high risk had levels of absolute risk reduction up to 3.5% instead 1.5%

(general cohort) and NNT of 35 instead 66 (general cohort).

Guideline recommendations. These recent trials have positioned PCSK9-mAbs as a third-line

therapeutic option, especially for people with very high risk and/or with LDL-C above

recommended goals despite maximally tolerated statins and ezetimibe. The positioning in

part reflects the higher costs of these therapies versus statins or ezetimibe. 14 15

Bile acid sequestrants

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Mechanism of action. Cholestyramine, colestipol and colesevelam are bile acid sequestrants

(BAS); they reduce the entero-hepatic pool of cholesterol and indirectly increase the

promotion of the synthesis of the LDLR, reducing the LDL-C levels between 18-25%.

Clinical research evidence. Despite benefits on LDL-C reduction, the evidence for

cardiovascular events reduction with these therapies is weak and precedes the

statin era 31,32

Guideline recommendations. BAS are recommended as an alternative in individuals requiring

further LDL-C lowering, such as those who cannot tolerate statins, or those in whom PCSK9-

mAbs may not be affordable and those with very high LDL-C such as those with familial

hypercholesterolaemia (FH) who often require multiple drug therapies. 14 15

Niacin

Mechanism of action. Niacin is an agonist of the HM74A receptors derived from

nicotinamide; it increases HDL-C levels between 25% and 35% and reduces LDL-C levels by

10% and 25%.

Clinical research evidence. In contemporary trials against a background of statin therapy

such as AIM-HIGH 33 and HPS2-THRIVE 34 trials showed no significant benefit with niacin

and with the combination of niacin/laropiprant respectively; in the case of the

niacin/laropiprant combination an excess of harm from infections, bleeding and

elevations in glucose was reported.

Guideline recommendations. Niacin is not routinely recommended in clinical guidelines

and is largely unavailable outside of north america.

CETP inhibitors

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Mechanism of action. Cholesteryl ester transfer protein (CETP) is overexpressed in

individuals with mixed dyslipidaemia; this protein mediates the heterotypic exchange of

cholesteryl esters from HDL to apo B lipoproteins and triglycerides from apo B to HDL

lipoproteins in the blood, by this mechanism CETP contributes to the mixed dyslipidaemia

profile (high TRL, low HDL and high small and dense LDL). Thus pharmacologic inhibition

of CETP can produce increases in HDL-C, along with reductions in levels of non-HDL

lipoproteins.

Clinical research evidence. Four CETP inhibitors have been tested in patients with

cardiovascular disease and terminated for varying reasons. Torcetrapib was terminated

after the observation of an excess risk in cardiovascular events and all-cause mortality

believed to be due to off target toxicity. 35 Dalcetrapib raised HDL-C by about 30% but had

no effect on LDL-C and was terminated for lack of clinical benefit but with no evidence for

harm. 36 Evacetrapib raised HDL-C by more than 100% and lowered LDL-C 31.1% as

calculated by the Friedewald formula, however, was stopped too for lack of clinical

benefit after 1,555 events had accrued from 12,092 patients during 26 months of follow

up. 37 The REVEAL trial with anacetrapib was the largest and longest of these trials (30,499

patients with 3,443 cardiovascular events recorded during 50 months of follow up) and

powered on LDL-C lowering as the effects of HDL-C raising (in this case > 100%) are

unknown. 38 During the course of the trial it was discovered that using Friedewald formula

calculated LDL-C overestimated the true LDL-C reduction versus direct LDL-C

measurements derived from ultracentrifugation and beta quantification. For instance, a

40% reduction by the former equated to about a 17% reduction via the latter method. In

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REVEAL, anacetrapib reduced LDL-C by 17% LDL-C using beta quantification and as the

baseline LDL-C was < 1.8mmol/L the reduction in risk was modest at 9% but directly

proportional to the absolute reduction in LDL-C or apoB.38 The development of

anacetrapib was terminated by the manufacturers.

Guideline recommendations. CETP inhibitors are not recommended in

guidelines.

Emerging therapies for LDL-C lowering

Bempedoic acid

Genetic studies suggest that lower ATP citrate lyase (ACL) activity (an enzyme present in

the cholesterol synthesis pathway) associates with a similar effect on lipid and CV disease

risk to those observed via lower HMGCoA reductase activity.39 Therefore ACL inhibition is

potentially viable target for LDL-C lowering and CV risk reduction.

Mechanism of action. Bempedoic acid is a prodrug that requires activation by the enzyme

very long-chain acyl-coA synthetase 1 present in the liver but absent in most other

tissues. It lowers LDL-C by inhibiting ATP citrate lyase (ACL), an enzyme involved in

cholesterol biosynthesis, which acts upstream of HMGCoA reductase (the target for

statins).

Clinical research evidence. Bempedoic acid at a dose of 180mg has been shown to reduce

LDL-C by 28.5% on top of ezetimibe among statin-intolerant patients with high LDL-C and

by 18.1% on top of high or moderate potency statins and with an adverse effect profile

similar to placebo apart from a small excess risk of gout. 40-42 Approvals for use in LDL-C

lowering are currently pending (Europe and USA). In combination with ezetimibe,

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bempedoic acid lowers LDL-C by as much as 48% 40 with a fixed dose combination

incorporating both drugs with no additional pill burden pending regulatory approvals. A

cardiovascular outcomes trial (CLEAR OUTCOMES) is ongoing in patients with LDL-C above

guideline recommended goals and statin intolerance at high risk of ASCVD.

Inclisiran

Mechanism of action. Mammalian cells possess an intrinsic pathway through which to

“silence” gene expression by the catalytic degradation of m-RNA through the RNA

induced silencing complex (RISC). Short double stranded RNA containing the

complementary sequence to the m-RNA (anti-sense strand) for the gene of interest bind

separate in cells through an enzyme called DICER with the anti-sense strand binding to

RISC and this complex induces degradation of multiple m-RNA transcripts, reducing the

production of the protein of interest. 43 Inclisiran, is a synthetic small interfering RNA

based therapeutic (siRNA) against PCSK9 m-RNA administered as a 1ml subcutaneous

injection. Chemical modification allows it to be rapidly taken up by the asialoglycoprotein

receptor in the liver reduces the dose needing to be administered thus reducing the

potential for side effects.

Clinical research evidence. In phase 2 studies two doses of 300mg inclisiran sodium

reduced LDL-C by 52.6% and over 40% reductions in apoB and non-HDL-C at 6 months on

top of statins. 44,45 The safety profile was comparable to placebo the time averaged

reduction in LDL-C exposure was more than 50% over 9 months. Currently a twice yearly

dosing regimen is being evaluated in 3 pivotal phase 3 lipid lowering trials expected to

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report in 2019, with an ongoing cardiovascular outcomes trial expected to complete in

2024.

LDL-C lowering therapies specific for Homozygous FH

Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic condition

characterised by markedly elevated LDL-C levels, premature atherosclerosis, aortic valve

disease and inadequate response to conventional drug therapy.46 Management includes

statins and PCSK9 inhibitors which work through increases in LDLRs provide more modest

LDL-C reductions and depend upon residual LDLR activity.47 However is severe cases with

extensive extracorporeal apheresis is the most effective but an invasive option.

Lomitapide

Mechanism of action. Lomitapide is a small molecule microsomal triglyceride transfer

protein (MTP) inhibitor, which acts to assemble apoB100-containing lipoproteins.48 This

results in fewer apo B particles in the circulation and hence lower LDL-C. Clinical Research

Evidence. The first phase 3 studies in HoFH evaluating safety and efficacy showed a robust

and durable reduction in LDL-C levels (50% at week 26 and 38% at week 78).49 The main

adverse events included gastrointestinal events, elevations of hepatic enzymes and an

increase hepatic fat.49 The efficacy and safety of long-term treatment are in particular the

implications of hepatic fat accumulation are being evaluated in an observational registry

of lomitapide-treated HoFH patients for at least 10 years.50

Guideline recommendations. Lomitapide is an approved treatment option for HoFH and

may reduce the need for apheresis. 14

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Mipomersen

Mechanism of action. Mipomersen is a second-generation antisense oligonucleotide which

binds apoB100 mRNA and triggers its degradation, resulting in the reduction of apoB

containing lipoproteins in the circulation. 51 A phase 3 study showed that mipomersen was

effective for HoFH with LDL-C levels decreasing by 21.3%. 52 The most commonly observed

adverse events were injection-site reactions. Other common side effects were elevations

in alanine aminotransferase and flu-like syndrome.52 A post-hoc analysis of prospectively

collected data showed that mipomersen use was associated with a lower risk of major

adverse cardiac event (85%).53 The clinical relevance of effects on the liver are uncertain

as theoretically hepatic fat accumulation could cause fibrosis or cirrhosis.

Guideline recommendations. Mipomersen is an approved treatment option for HoFH and

may reduce the need for apheresis. 14

Evacinimab

Mechanism of action. Angiopoietin-like 3 protein (ANGPTL3) is an intrinsic inhibitor of

both lipoprotein lipase and endothelial lipase in humans.54

Clinical Research Evidence. Pharmacologic inhibition of ANGPTL3 causes a dose-dependent

reduction in triglycerides of up to 76% and LDL-C up to 23% independent of the LDLR (the

mechanism remains unknown). 55 56 Evinacumab is the first in class monoclonal antibody

that inhibits ANGPTL3, was granted therapy designation for the treatment of HoFH by the

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FDA in 2017, and is being evaluated in a Phase 3 study for long-term safety and

tolerability.

Lipoprotein(a)

Lp(a)] is a LDL-like particle, synthesised by hepatocytes, consisting of a cholesterol-rich LDL

moiety linked to an apolipoprotein(a)- ((apo(a)); Lp(a) is subject to tight genetic control. 57

Evidence of pathogenicity. Elevated levels of Lp(a) (>30 mg/dL) have been associated in

epidemiological studies with a higher risk of cardiovascular disease and calcific aortic valve

stenosis independent of LDL-C.58 59 Genome-wide association studies and mendelian

randomisation studies support a causal relationship between high Lp(a) levels and

myocardial infarction, cerebrovascular events, peripheral arterial stenosis and aortic valve

calcification.60 61 62 Lp(a) has pro-atherogenic effect and induces pro-inflammatory

responses via accumulation of oxidized phospholipids and may exert prothrombotic

effects via the plasminogen-like apo(a) moiety. 63 63

Non-specific Lp(a) lowering therapies

Lifestyle and dietary interventions have minimal or no effect on Lp(a) levels. Nicotinic acid,

mipomersen and CETP inhibitors decreases levels by 25%, 40% and 35% respectively, and

PCSK9-mAbs decrease Lp(a) by around 25%. 64 The proportional reduction in Lp(a) is more

modest among those with higher Lp(a) levels. Lp(a) is a marker of high risk and trials of

PCSK9-mAbs demonstrate greater absolute risk reduction among those with higher Lp(a)

levels, but it is uncertain what portion if any of the CV benefits observed are related to

Lp(a) lowering or simply reflect LDL-C reduction in a higher risk population. 65

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Specific Lp(a) lowering therapies

Antisense oligonucleotide against apo(a)

Mechanism of action. Antisense oligonucleotides are a class of single-stranded RNA

therapies which bind to mRNA coding for the target proteins and leading to the catalytic

degradation of mRNA by ribonuclease H. AKCEA-APO(a)-LRx, is a second-generation

antisense oligonucleotide designed to reduce the synthesis of apo(a) in the liver and

consequently reduce the level of Lp(a) in plasma. 66

Clinical research evidence. A phase 1 study among individuals with high Lp(a) levels

showed a dose dependent reduction in Lp(a) of 68%, 80%, and 92% with a weekly dosing

schedule, as well as more modest decreases in oxidized phospholipids, (OxPL-apoB). 67

Phase 2 studies have been completed evaluating the safety, dose range and dosing

interval in patients with high levels of Lp(a) and cardiovascular disease. As it is unknown

whether lowering Lp(a) per se reduces CV events a phase 3 registration outcomes trial is

due to start in late 2019- 2020 to evaluate the effect of AKCEA-APO(a)-LRx in patients with

high Lp(a) and established cardiovascular disease. Unlike LDL-C, lowering Lp(a) has not

been demonstrated to be beneficial hence this therapy will not be approved for Lp(a)

lowering until the completion of outcomes trial.

Guideline recommendations. Among those with high Lp(a) the focus is on lifestyle

aggressive control of traditional risk factors.

Triglycerides

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Mechanism of pathogenicity. Increasing evidence implicates triglyceride rich lipoproteins

(TRL), including very low-density lipoproteins (VLDL), intermediate density lipoproteins

(IDL), chylomicrons and their remnants, in the pathogenesis of atherosclerotic

cardiovascular disease. This is supported primarily by reports that (i) both fasting and non-

fasting triglyceride levels independently associate with prospective cardiovascular risk in

large cohort studies, 68 (ii) hypertriglyceridemia identifies patients with a high residual

cardiovascular risk despite achieving low levels of low-density lipoprotein cholesterol (LDL-

C) with intensive statin therapy 69 and (iii) the demonstration that TRLs exert

proatherogenic effects in cell and animal studies.70,71 From a mechanistic perspective, it is

likely that the cholesterol content of TRLs continue to underscore their proatherogenic

properties. Recent insights from mendelian randomisation studies demonstrate that

genetic polymorphisms influencing the activity of factors that regulate TRL metabolism

associate with cardiovascular risk, further supporting a causal role for TRLs in

atherosclerosis.72

Guideline recommendations. The presence of elevated triglyceride levels in high

cardiovascular risk patients should primarily be treated with statin therapy, aimed at

intensive lowering of both apoB, non-HDL-C and LDL-C. 14,15

Fibrates

Mechanism of action. Fibrates are modest pharmacological agonists of the peroxisome

proliferator activated receptor- (PPAR-) and have been used as a lipid modifying

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therapy for more than fifty years. They produce lowering of triglycerides, LDL-C and C-

reactive protein, in addition to modest elevation of HDL-C.

Clinical research evidence. Numerous fibrates have been investigated in large scale clinical

trials, both prior to and in combination with contemporary use of statin therapy. While

these studies have produced variable results in terms of their impact on cardiovascular

event rates, meta-analyses suggests that cardiovascular benefit is more likely to be

observed in patients with elevated triglyceride levels.73 74 As side effects have been

observed when more potent PPAR- agonists have been evaluated,75 development of

selective PPAR- modulators (SPPARMs) provides the opportunity to achieve desirable

lipid effects, whilst minimising side effects. The first SPPARM, pemafibrate, lowers

triglyceride levels by more than 30% and is well tolerated.76 It has now proceeded to a

large cardiovascular outcomes trial (PROMINENT), in which its impact will be determined

in patients with both hypertriglyceridemia and low HDL-C levels.77

Guideline recommendations. Use of fibrates are recommended for management of

hypertriglyceridemia. 14

Omega-3 fatty acids

Mechanism of action. Omega-3 fatty acids exert favourable biological effects on

inflammatory, oxidative, thrombotic and arrhythmic factors implicated in cardiovascular

disease.78 The finding that red blood cell omega-3 fatty acid levels, an indicator of tissue

levels, directly correlate with cardiovascular risk, 79 suggests that achieving adequate

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tissue concentrations are likely to be an important requisite for omega-3 fatty acids to be

cardioprotective.

Clinical research evidence. Cohort studies suggest that higher consumption of

polyunsaturated fatty acids associate with lower cardiovascular risk80 and in a trial of

dietary supplementation with 1g of omega-3 fatty acids resulted in fewer cardiovascular

events in a post-MI population, which preceded modern use of statin therapy. 81 Over the

course of the last decade a number of clinical trials have attempted to determine whether

omega-3 fatty acid administration will be beneficial. The majority of these studies have

failed to demonstrate reductions in CV risk, which has been further confirmed by meta-

analyses.82 However, these studies have varied markedly in terms of clinical setting,

patient phenotype and dose of omega-3 fatty acids administered. More recent trials have

provided important insights with regard to the factors influencing the role of omega-3

supplementation in high cardiovascular risk patients.

Two major studies reported the impact of relatively low doses of omega-3 fatty

acids on cardiovascular outcomes in 2018. In a primary prevention study involving 25,871

individuals (VITAL), administration of marine omega-3 fatty acids 1 g daily had no impact

on the primary cardiovascular composite endpoint.83 While a 28% reduction in myocardial

infarction, a secondary endpoint, was reported, the clinical implications of this finding are

uncertain. Similarly, a trial of 15,480 patients with diabetes and no evidence of

atherosclerotic cardiovascular disease (ASCEND) demonstrated no reduction in

cardiovascular events in those treated with omega-3 fatty acids 1 g daily.84

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Clinical trials of higher doses of omega-3 fatty acids have proven to be more

promising with regards to their impact on cardiovascular events. An open-label study of

EPA 1.8 g daily in 18,645 Japanese, statin-treated hypercholesterolemic patients (JELIS)

demonstrated a 19% reduction in coronary events, despite minimal triglyceride lowering.85

The lowest event rate was observed in patients with the highest plasma EPA

concentrations.86 This result has led to increasing use of EPA for cardiovascular prevention

in Japan. A subsequent multinational trial in high cardiovascular risk patients with modest

hypertriglyceridemia (REDUCE-IT) demonstrated that administration of pure EPA

(Icosapent) 4 g daily reduced cardiovascular events by 25%,, with no evidence of

association between triglyceride lowering and clinical benefit.87

Ongoing studies. The STRENGTH study 88 is comparing the effects of the carboxylic acid

form of EPA/DHA 4 g and corn oil placebo daily in high cardiovascular risk patients with

both moderate hypertriglyceridemia and low levels of high-density lipoprotein cholesterol

(HDL-C). This form of omega-3 fatty acid does not require hepatic conversion and as a

result produces similar tissue EPA levels as found with Icosapent. It will provide the

opportunity to determine whether administration of high doses of combinations of

omega-3 fatty acids will produce a similar cardiovascular benefit to that observed with

administration of EPA alone.

Guideline recommendations. Daily dietary consumption of omega-3 fatty acids is

integrated into many treatment guidelines for cardiovascular prevention. High dose

administration of omega-3 fatty acids are recommended as a treatment option for

management of hypertriglyceridemia. 14 The results of recent cardiovascular outcomes

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trials targeting high dose omega-3 fatty acids to patients with baseline

hypertriglyceridemia are likely to be incorporated into future guidelines.

Newer approaches to Triglyceride lowering

Lipoprotein lipase (LPL) plays a pivotal role in metabolism of TRLs within the circulation.

Characterisation of factors (apoCIII, angiopoietin like protein 3/4 [ANGPLT3/4]) that

modulate LPL activity have been demonstrated to impact circulating triglyceride levels,

with evidence from genomic studies that polymorphisms influencing these factors

associate with cardiovascular risk.89,90 Beyond their role in TRL metabolism, mechanistic

studies have demonstrated that apoCIII and ANGPTL may also regulate inflammatory and

lipid transporting factors, which may also influence cardiovascular risk.91-93 Accordingly,

there is considerable interest in development of therapeutic approaches targeting these

factors.

Antisense oligonucleotides targeting apoCIII (volanesorsen) have been evaluated in

early lipid trials, resulting in profound triglyceride lowering. This has been particularly

important in familial chylomicronemia syndrome, providing an important new therapeutic

for these patients who are prone to recurrent episodes of pancreatitis.94 While this agent

has been demonstrated to reduce platelet counts, the underlying mechanism and clinical

implication remains unknown. Whether it will be evaluated in much broader,

hypertriglyceridemia population is uncertain at this point. A range of ANGPTL inhibitory

strategies, including monoclonal antibodies (evinacumab) and RNA silencing approaches,

are undergoing evaluation in clinical trials.

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High-Density Lipoproteins

Evidence of pathogenicity. Considerable interest has focused on development of HDL

targeted therapies on the basis of observations of an inverse relationship between HDL-C

levels and cardiovascular risk in population studies and evidence that HDL is

atheroprotective in preclinical studies. 95 In addition to promotion of reverse cholesterol

transport, HDL has been demonstrated to modulate inflammatory, oxidative and

thrombotic pathways implicated in cardiovascular disease.

Clinical research evidence. Contemporary studies of niacin, the most effective HDL-C

raising agent available in clinical practice, have failed to demonstrate any benefit on

clinical outcomes 33,34 and cholesteryl ester transfer protein (CETP) inhibitors, the most

profound HDL-C raising agents studied in clinical trials, have had variable effects, including

toxicity,35 and modest benefit (discussed earlier).36-38 The failure of HDL-C raising to

produce clinical benefit is supported by mendelian randomization studies, which suggest

that HDL-C per se does not play a causal role in atherosclerotic disease.96

More recent efforts have focused on targeting the functional quality of HDL. This is

supported by reports that measures of HDL function with regard to cholesterol efflux97

and anti-oxidant activity98 independently associate with cardiovascular risk. Studies of

infusing HDL mimetics have provided an attempt to administer functional forms of HDL.

While an early report of regression of coronary atherosclerosis was reported with HDL

mimetic administration after an acute coronary syndrome,99 this no longer proved to be

the case in more recent studies of patients treated with high potency statins. 100 101 A large

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cardiovascular outcomes trial is currently evaluating the impact of a functional HDL

mimetic (CSL-112) with considerable cholesterol efflux activity 102 on clinical events.

Guideline recommendations. Lifestyle measures represent the cornerstone to produce

modest increases in HDL-C. 14 Low levels of HDL-C identify patients at higher risk of future

cardiovascular events and are useful in the triage of patients for more potent LDL-C

lowering with statins. Given the lack of benefit observed from clinical trials therapeutic

approaches directed at HDL-C raising are not currently recommended.

Summary

Lipid modification therapy to prevent IHD targets LDL-C lowering, firstly through statins

and then with add on therapies such as ezetimibe, bile acid absorption inhibitors and

PCSK9-mAbs based on clinical indications, cost and availability (Figure 2). Emerging

therapies such as bempedoic acid and inclisiran may offer additional therapeutic options

for LDL-C lowering indications within a few years but evidence for IHD prevention will take

longer. Currently for individuals with elevated Lp(a) the focus of lipid modification centers

on more aggressive reduction in LDL-C but RNA based therapies specifically targeting Lp(a)

may become the preferred option for these patients if cardiovascular risk reduction is

demonstrated in the future (Figure 2). For those with elevated triglycerides and on

optimal doses of statins high dose EPA targeting residual risk from triglyceride offers a

validated approach to reducing the risk of IHD and other approaches may emerge shortly

(Figure 2). One size clearly does not fit all and the lipid field has never been more

promising from multiple therapies that lower LDL-C to therapies targeting other lipid

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fractions as well as the emergence of injectable therapies with infrequent dosing

regimens. The challenge now will be how to prioritise these different approaches.

Contributions

KKR conceived the original scope of this manuscript. All authors approved this. Each

author wrote specific sections and all authors have critically reviewed and revised the final

manuscript and thus contributed equally to the final output.

Acknowledgements

KKR acknowledges support from the Imperial NIHR Biomedical Research Centre

Disclosures

KKR reports personal fees for consultancy from Abbvie, Amgen, Astra Zeneca, Sanofi,

Regeneron MSD, Pfizer, Resverlogix, Akcea, Boehringer Ingelheim, Novo Nordisk, Takeda,

Kowa, Algorithm, Cipla, Cerenis, Dr Reddys, Lilly, Zuellig Pharma, Bayer, Daiichi Sankyo,

The Medicines Company; Esperion and research grant support from Pfizer, Amgen, Sanofi,

Regeneron and MSD.

PC reports grants from Amgen and Sanofi and personal fees for consultancy from Amgen,

Sanofi and Boehringer Ingelheim.

ECM reports personal fees for consultancy from Abbott, Amgen, Boehringer Ingelheim,

Merck Sharp and Dohme, Novo Nordisk,Pfizer, Servier, Takeda grants from Boehringer

Ingelheim, Bristol Myers Squibb, Astra Zeneca, Janssen-Cilag, Kowa, Eli Lilly, Novartis,

Roche, Sanofi, Servier, Takeda and Theracos.

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SJN reports receiving research grants from AstraZeneca, Amgen, Anthera, Eli Lilly,

Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche,

Sanofi-Regeneron and Liposcience and is a consultant for AstraZeneca, Akcea, Eli Lilly,

Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion

and Boehringer Ingelheim.

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Legends

Figure 1

Lipid targets, mechanism via which these could be altered and current or emerging therapies

directed against these targets

Footnotes

LDL-C: Low-density lipoprotein cholesterol, Lp(a): lipoprotein(a), LDLR- lo density

lipoprotein receptor, PCSK9 mAbs: Proprotein convertase subtilisin/kexin9 monoclonal

antibodies ; CETP: Cholesteryl ester transfer protein, Apo-CIII: Apolipoprotein C-III,

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ANGPLT-3: Angiopoietin like protein 3, SPPARMS: Selective receptor modulator of the

peroxisome proliferator-activated receptor

Figure 2

Approaches to lowering cardiovascular risk through lipid modification: current strategy and

potential future options

Footnotes

LDL-C: Low-density lipoprotein cholesterol, TG: Triglycerides, Lp(a): lipoprotein(a),

mAbs-PCSK9: monoclonal antibodies to Proprotein convertase subtilisin/kexin9; CETP: Cholesteryl

ester transfer protein; EPA: Eicosapentaenoic acid; Apo-CIII: Apolipoprotein C-III, ANGPLT-3:

Angiopoietin like protein 3, SPPARMS: Selective receptor modulator of the peroxisome

proliferator-activated receptor, Lp(a) lipoprotein(a)

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