State-of-the-art lipid-lowering for secondary prevention - focus on drug therapy

Abbreviations

ACS                 acute coronary syndrome

ASCVD            atherosclerotic cardiovascular disease

CK                   creatinine kinase

DLCN              Dutch Lipid Clinic Network

ECG                 electrocardiogram

FH                   familial hypercholesterolaemia

HDL                high-density lipoprotein

HMG-CoA       3-hydroxy-3-methyl-glutaryl-coenzyme A reductase

LDL                 low-densitity lipoprotein

NPC1L1           Niemann-Pick C1-like protein

NSTEMI          non-ST-elevation myocardial infarction

PCI                  percutaneous coronary intervention

PCSK9            proprotein convertase subtilisin/kexin type 9 inhibitors

RCT                 randomised controlled trial

SAMS              statin-associated muscle symptoms

SOP                 standard operating procedure

Introduction

A 57-year-old male was admitted to the emergency room by local ambulance services for suspected acute coronary syndrome (ACS). Coronary angiography revealed severe three-vessel disease (3VD) without a culprit lesion. The by then asymptomatic patient was then transferred to the ward. On the day after admission, a risk assessment including the patient’s history, his risk factors and routine laboratory assessment was performed. He reported a non-ST-segment myocardial infarction (NSTEMI) with 3x percutaneous coronary intervention (PCI) at the age of 47. As risk factors he mentioned a well-controlled arterial hypertension and a former nicotine abuse. He is currently only taking low-dose aspirin and an ACE inhibitor. His father died at the age of 41 from a heart attack, his mother had a stroke at 70 and his brother had a heart attack at the age of 45. The lipid panel showed a total cholesterol of 279 mg/dL (7.2 mmol/L), a high-density lipoprotein (HDL) cholesterol of 31 mg/dL (0.8 mmol/L), a low-density lipoprotein (LDL) cholesterol of 219 mg/dL (5.6 mmol/L), triglycerides at 186 mg/dL (4.8 mmol/L) and a lipoprotein(a) at 29 nmol/L. The patient was put on a combination pill including atorvastatin 80 mg and ezetimibe 10 mg once daily and referred to the cardiovascular lipid outpatient clinic for re-evaluation of cholesterol values and screening for familial hypercholesterolaemia (FH).

Decades of research including experimental studies, epidemiological observations and Mendelian randomisation studies as well as numerous randomised controlled trials (RCTs) have consistently shown a strong relationship between measured LDL-C levels and incidence of atherosclerotic cardiovascular disease (ASCVD) as well as a log-linear relationship between LDL-C changes and ASCVD risk [1, 2, 3]. Together with Mendelian randomisation studies showing the safety and benefits of lifelong exposure to low LDL-C, the “the lower the better” principle for LDL-C in secondary prevention was postulated. The current 2019 European Society of Cardiology (ESC) guidelines for the management of dyslipidaemias suggest a target LDL-C of 55 mg/dL (1.4 mmol/L) or lower and a minimum reduction of LDL-C >50% from baseline levels in all patients with established ASCVD [4]. Within this review we want to highlight the currently available drug treatment options to achieve those targets in order to minimise residual risk due to uncontrolled hypercholesterolaemia. We will focus on approved and available medications for patients with established ASCVD in Europe. Table 1 gives an overview of currently available lipid-lowering medication.

Table 1. Overview of the currently approved and available drug treatment options in Europe to achieve LDL-C target levels in patients with established atherosclerotic cardiovascular disease.

Statins

Statins are the cornerstone of LDL-C reduction in secondary prevention. They inhibit cholesterol synthesis in the hepatocyte by inhibiting HMG-CoA reductase, the rate-limiting step in hepatic cholesterol synthesis. This causes reduced hepatic cholesterol production and upregulation of LDL receptors on hepatocytes, thus causing a reduction in circulating LDL-C. The achieved LDL-C-reduction is mainly dependent on the type of statin and dosage used, while inter-individual variations in the response to statins have been described. The ESC and scientific community have defined “high-intensity statin treatment” as the type and dose of a statin that reduces LDL-C by >50%, which can, in most cases, safely be achieved by atorvastatin 40-80 mg and rosuvastatin 20-40 mg once daily. Besides its LDL-C reducing effects, pleiotropic effects including anti-inflammatory and anti-oxidant effects have been described [5]. The clinical impact of these effects currently remains unclear.

A great many large-scale cardiovascular outcome trials using different types and doses of statins have been published, which cannot be summarised here in detail. The famous meta-analysis of individual participant data by the Cholesterol Treatment Trialists’ Collaboration included five trials with >39,000 participants and five years of follow-up comparing high-intensity versus less intense statin treatment and 21 trials with >129,000 participants comparing statin treatment versus control with a similar follow-up [1]. More intense statin treatment was associated with a mean average LDL-C reduction of about 20 mg/dL (0.51 mmol/L), translating into a 15% further reduction of major vascular events (including a 13% reduction in coronary death or non-fatal MI, a 19% reduction in coronary revascularisation and a 16% reduction of ischaemic stroke).

The effects of an LDL-C reduction per 40 mg/dL (1.0 mmol/L) in patients comparing low- versus high-intensity therapy were similar to those comparing statin versus control. Combining both trials, similar proportional effects on major vascular events (RR 0.78; 95% CI: 0.76-0.8) per 40 mg/dL (1.0 mmol/L) reduction were found regardless of patient type or baseline LDL-C. Overall, a 10% reduction in all-cause mortality was seen per 40 mg/dL (1.0 mmol/L) LDL-C reduction.

Statins are in general very well tolerated; however, some adverse events including myopathy, diabetes and haemorrhagic stroke as well as some drug-drug interactions need to be mentioned [6]. While cases of rhabdomyolysis have been reported and were estimated to occur at a rate of 1-3 cases/100,000 patient-years, most patient-reported muscle symptoms are not accompanied by significant elevations in creatinine kinase (CK) and are summarised as “statin-associated muscle symptoms (SAMS)”. Several approaches exist in the handling of such patients, including CK measurements, use of a clinical scoring system [7], statin washout and rechallenge with another type of statin at the recommended or a lower dose and alternate day prescription [4]. Inability to tolerate two or more statins in different dosages is often classified as “statin intolerance”. Statin treatment, especially in higher doses in the elderly, increases the risk of new-onset diabetes (number needed to harm 255 per 4 years of treatment). Still, the above described benefits of statin treatment clearly outweigh the small increase in diabetes diagnosis.

The meta-analysis highlighted above also suggested a 21% relative increase in haemorrhagic stroke per 40 mg/dL (1.0 mmol/L) LDL-C reduction, an effect that was outweighed by the decrease in other stroke forms. All statins except rosuvastatin and pravastatin undergo metabolism via cytochrome P450 pathways; thus, parallel medication with other drugs metabolised via CYP pathways may increase the risk of myopathy and rhabdomyolysis.

The previously mentioned strikingly positive, reproducible and constant effects of and decades of experience with high-intensity statins have rendered them the cornerstone for secondary prevention in ASCVD. In this patient cohort, only high-intensity statins with an expected LDL-C lowering of at least 50% should be used (atorvastatin 40-80 mg, rosuvastatin 20-40 mg). Current ESC guidelines recommend them as first-line therapy with a IA recommendation [4]. Several institutions have now moved to an initial dual lipid-lowering approach in patients where the expected LDL-C lowering will miss the therapeutic goal of <55 mg/dL.

Ezetimibe

As a cholesterol absorption inhibitor, ezetimibe inhibits intestinal cholesterol uptake by interaction with the Niemann-Pick C1-like protein (NPC1L1). This reduction in cholesterol delivery to the liver causes an upregulation of LDL receptors on hepatocytes, leading to further reduction in circulating LDL-C. Ezetimibe as a monotherapy in its recommended dose of 10 mg once daily is associated with an approximately 18.5% reduction of circulating LDL-C, while addition of ezetimibe to statin therapy reduced LDL-C by around 23% [8]. Several long-term observations from randomised trials suggest a safety profile not significantly different from placebo [9].

The only outcome trial in ASCVD patients and the only outcome trial testing specifically the effects of ezetimibe was IMPROVE-IT, in which ezetimibe 10 mg once daily was added to a therapy with simvastatin 40 mg in more than 18,000 patients after an ACS [10]. Patients treated with simvastatin alone reached on average an LDL-C of 70 mg/dL (1.8 mmol/L), while those in the combination therapy group reached an LDL-C of 55 mg/dL (1.4 mmol/L), translating into a small, albeit significant reduction of cardiovascular events. Therefore, IMPROVE-IT had several important implications for our daily practice. On the one hand, it was shown that a non-statin therapy reducing LDL-C translates into a reduction of CV events. On the other hand, the results indicated that an even lower achieved LDL-C than suggested by the guidelines at that point further reduced CV events.

These data caused the ESC to recommend ezetimibe as a second-line therapy for ASCVD patients not achieving LDL-C goals with the maximum tolerated dose of a statin with a IB recommendation and in those not tolerating statin treatment with a IIa C recommendation [4]. It can be expected that a dual lipid-lowering therapy consisting of a high-dose statin and ezetimibe will result in an LDL-C reduction of approximately 65%. As the LDL-C reduction in response to high-intensity statin treatment alone can be predicted to be about 50%, several institutions (including our own) have implemented standardised operating procedures (SOPs) suggesting an initial dual lipid-lowering therapy with a high-intensity statin and ezetimibe in patients with an (untreated) LDL-C of above 100 mg/dL during the initial hospitalisation [11]. As observational studies continue to show low guideline adherence, in our opinion it is of the utmost importance that cardiovascular centres lead by example by initiating evidence-based, strong lipid-lowering therapies in response to baseline LDL-C levels during the initial hospital admission, especially in view of the fact that ezetimibe is now available in generic form.

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9 inhibitors)

It took only 14 years from the first description of the PCSK9 gene in a family with severe FH to the publication of the results of the first phase III RCT evaluating PCSK9 antibody therapy in patients with ASCVD. The success story started in 2003, when a family with PCSK9 gain of function resulting in a very severe form of FH was described [12]. Soon thereafter, a study involving individuals with a PCSK9 loss of function resulting in low PCSK9 activity, very low LDL-cholesterol and a subsequent low prevalence of ASCVD was published [13]. The latter rendered PCSK9 inhibition an interesting therapeutic option, as patients with PCSK9 loss of function were healthy, exhibited very low LDL-C levels and a strongly reduced ASCVD prevalence. About a decade later, the first monoclonal antibodies targeting PCSK9 were available - two fully humanised ones (evolocumab and alirocumab) as well as one partially humanised antibody (Bococizumab), the latter one associated with the production of neutralising antibodies reducing its LDL-lowering abilities and causing the cessation of its development [14]. Upon binding of LDL to the LDL receptor on the hepatocyte surface, the newly formed LDL receptor-LDL complex is internalised within endosomes, which causes a conformational change leading to the release of LDL from the LDL receptor. The LDL receptor is then recycled back to the plasma membrane. Binding of PCSK9 to this complex prevents this conformational change causing lysosomal degradation of the LDL receptor, thereby leading to elevated circulating LDL-C. This mechanism and the observational data of patients with PCSK9 loss of function mutations render PCSK9 inhibition a very promising approach to lipid lowering. As statin treatment upregulates PCSK9, a combination therapy seems ideal and yields an approximate 75% reduction in circulating LDL-C, while PCSK9 monotherapy decreases LDL-C by around 50-60%.

Two major phase III cardiovascular outcome RCTs have been conducted thus far - the FOURIER trial [15] and the ODYSSEY OUTCOMES trial [16], evaluating the efficacy and safety of the subcutaneously injected monoclonal antibodies evolocumab and alirocumab in addition to statin background therapy, respectively. The FOURIER study included patients with stable coronary artery disease (CAD), peripheral artery disease or stroke, while the ODYSSEY trial recruited patients after a recent ACS. Each trial had a relatively short follow-up of 2.2 and 2.8 years, LDL-C was reduced to 30 mg/dL (0.8 mmol/L) and 48 mg/dL (1.2 mmol/L), respectively, and both showed a reduction in the primary cardiovascular composite endpoints of 15-20%. The most prevalent side effects included injection site reactions and flu-like symptoms. Early studies suggested patient-reported neurocognitive effects, which prompted the EBBINGHAUS trial specifically aimed at evaluating neurocognitive function changes, which yielded neutral results comparable to FOURIER and ODYSSEY [17]. Very few cases of antidrug antibodies against evolocumab and alirocumab have been reported thus far, without any effects on LDL-C reduction described.

Thus, the 2019 ESC guidelines suggest PCSK9 inhibitor therapy in secondary prevention in patients with ASCVD not achieving their LDL-C goal on a maximum tolerated dose of a statin and ezetimibe with a IA recommendation as well as in very high risk FH patients with ASCVD or another major risk factor with a IC recommendation [4]. In patients who do not tolerate a statin-based regimen at any dosage even after rechallenge, current guidelines suggest adding a PCSK9 inhibitor to ezetimibe therapy (IIb level C). Heightened costs, although constantly declining, and rather short-term follow-up data regarding safety compared to established lipid-lowering therapies have thus far limited the use of PCSK9 inhibitors to high-risk patients with established ASCVD and those with FH.

Inclisiran is a small interfering RNA molecule targeting PCSK9 synthesis given twice within three months and every six months thereafter which can dose-dependently reduce LDL-C levels by up to 50%, with no specific serious adverse events observed [1]. A cardiovascular outcome trial (HPS4/TIMI65/ORION4) is currently being conducted.

Bempedoic acid

Bempedoic acid is a novel, oral small molecule inhibiting cholesterol synthesis within the liver by blocking adenosine triphosphate citrate lyase, an enzyme upstream of HMG-CoA reductase. Bempedoic acid is a prodrug and requires activation by the enzyme very long-chain acyl-CoA synthetase 1, which is present in the liver but absent in most peripheral tissues. In contrast to statins, inhibition of cholesterol biosynthesis is liver-specific, which results in reduced side effects, in particular a reduction of muscle symptoms as compared to statins. Recently, both the Food and Drug Administration and the European Medicines Agency approved the use of bempedoic acid either alone or as a fixed dose combination with ezetimibe for patients with heterozygous FH or established ASCVD who require additional LDL-C lowering (USA) or for patients with primary hypercholesterolaemia or mixed dyslipidaemia unable to reach LDL-C goals with the maximum tolerated dose of a statin or in patients who are statin intolerant or have a contraindication for statins (EU) [18]. The recommended dose of bempedoic acid is 180 mg once daily either alone or in combination with ezetimibe 10 mg together with or without high-dose statin therapy.

After completion of preclinical studies as well as the phase I and phase II study programmes, the phase III CLEAR programme was initiated testing bempedoic acid in several patient populations as a monotherapy as well as in addition to established treatments. The addition of bempedoic acid to maximally tolerated statin therapy reduced LDL-C levels by 16.5% and 17.2%, while administration as a combination therapy with ezetimibe was associated with a 36.2% reduction. Of great interest is the observation that treatment with the combination of bempedoic acid and ezetimibe on top of statin treatment was associated with a 35% reduction in high-sensitivity C-reactive protein (hsCRP). When given as monotherapy in patients with documented statin intolerance (≥2 different statins) it reduced LDL-C levels by 23% [19].

Currently, a large-scale phase III cardiovascular outcome trial (CLEAR OUTCOMES, NCT02993406) including more than 14,000 patients with established ASCVD or high risk for ASCVD and documented statin intolerance is on its way. Recruitment has been completed and the estimated study completion date is December 2022. Regarding adverse events, the CLEAR HARMONY and CLEAR WISDOM trials suggested an increased risk in upper respiratory tract infections, muscle spasms, hyperuricaemia and gout, tendon rupture, back pain, abdominal pain and discomfort, bronchitis, extremity pain, anaemia as well as liver enzymes. The ongoing phase III study will provide further insights into possible adverse effects.

While waiting for the results of the phase III outcome trial, the current role of bempedoic acid might be for ASCVD patients or FH patients not reaching LDL-C goals on established dual therapy (high-dose statin + ezetimibe) as well as for ASCVD patients with documented statin intolerance who do not qualify for PCSK9 inhibitor therapy according to local standards. The results of the currently running phase III trial are eagerly anticipated in order to see whether treatment with bempedoic acid will reduce ASCVD events as hypothesised according to the “the lower the better” principle. This will define its role in the current lipid-lowering drug armamentarium.

Patient follow-up

Two months after the index event, the patient was seen in our cardiovascular lipid outpatient clinic. He had no complaints. He underwent a three-week cardiac rehabilitation programme and has taken his medication. With the combination therapy of atorvastatin 80 mg and ezetimibe 10 mg, his LDL-C was 120 mg/dL, thus well above the goal of 55 mg/dL. He was prescribed a PCSK9 inhibitor, underwent injection training and applied the first injection under supervision. Due to his young age at the index event and the remarkable family history for premature coronary disease, he was screened for FH using the Dutch Lipid Clinic Network criteria (DLCN, www.fhscore.eu) [20]. His score was 6, translating into probable FH, which prompted genetic testing. At his second follow-up visit after another two months, he presented in a very good condition and reported no side effects from his treatment. His LDL-C was 52 mg/dL, thus within the desired goal of the ESC. His genetic test showed a mutation in the LDL-receptor gene associated with FH. This prompted a family cascade screening. Both the mother of the patient and his 20-year-old daughter exhibited the same LDL-receptor mutation. Lipid-lowering therapy was escalated in the mother and started in the daughter, after careful education regarding the contraindications of statin therapy during pregnancy. The diagnosis and treatment of FH are however beyond the scope of this article. We therefore recommend further literature published by the ESC and the European Atherosclerosis Society to the reader [20].