Cardiovascular disease (CVD) is the leading cause of death in Portugal1 and in other developed countries. Various risk factors for atherosclerotic (atherothrombotic) CVD are known, one of the most important of which is dyslipidemia. In recent years, findings from epidemiological, genetic, pathophysiological and clinical studies have shown unequivocally that there is a clear, consistent and progressive association between higher plasma low-density lipoprotein (LDL) cholesterol (LDL-C) levels and atherosclerotic CVD, confirming that LDL-C is a direct causal factor of the disease.2

Furthermore, there is incontrovertible evidence that reducing LDL-C proportionally reduces the risk of cardiovascular (CV) events.3,4 The guidelines therefore consistently recommend that lipid-lowering therapy should be adjusted in accordance with target LDL-C levels, which should be individualized on the basis of the patient's CV risk.5–7

However, various studies have shown that in a high proportion of patients, CV risk factors are not adequately controlled.8 The Portuguese results of the Dyslipidemia International Study (DYSIS) showed that 63% of patients treated with statins did not reach target LDL-C levels.9 This poor LDL-C control is due to many factors, which may be dependent on the patient (poor adherence and discontinuation of therapy), on the physician (particularly clinical inertia), or on the treatment (interindividual variations in and limits to the efficacy of lipid-lowering therapy).5,10

In recent years, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (PCSK9i) have emerged as a new therapeutic option that can consistently achieve significant (∼50-60%) reductions in LDL-C levels, which in clinical trials translates into an additional reduction in risk for CV events.11–13 However, PCSK9i are a costly therapy and should therefore be used only after careful consideration of their cost-effectiveness and their impact on the sustainability of the health system.14

This consensus document, produced by specialists in cardiology, endocrinology and internal medicine and sponsored by the corresponding medical societies, aims to summarize the main data on the clinical use of PCSK9i and to make recommendations suitable for the situation in Portugal on the profile of patients who may benefit most from this therapy.

The association between LDL-C levels and the development of atherosclerosis (the ‘LDL hypothesis’) was established decades ago, based on numerous epidemiological studies demonstrating a continuous and linear relationship between exposure to high plasma LDL-C levels and risk of CV events.15

More recent data from genetic studies, particularly those using Mendelian randomization, have consistently shown that multiple genetic variants that lead to higher LDL-C levels are associated with increased CV risk,16,17 and confirm that LDL-C levels play a causal role in the development of CVD.2

The most significant evidence on the role of LDL-C as a cause of CVD comes from randomized clinical trials that demonstrate a proportional relationship between the extent of LDL-C reduction and reduction of CV risk. A meta-analysis of 26 trials involving 17 000 individuals on statin therapy revealed a 22% reduction in risk of major CV events per 1.0 mmol/l (39 mg/dl) reduction in LDL-C, establishing the concept of ‘the lower, the better’.3,18,19 The benefit of lipid-lowering therapy is less in the first year of treatment, when the risk reduction is ∼10%, but is consistently 22-24% per mmol/l in subsequent years.20,21 The risk reduction is seen with different therapeutic options (statins, ezetimibe, resins, PCSK9i or ileal bypass surgery) that have in common the effect of reducing LDL-C by upregulating LDL receptor (LDLR) expression in hepatocytes, as demonstrated by a meta-analysis of 49 trials including 312 175 patients and 39 645 events.4 Finally, clinical trials assessing progression of coronary disease by intravascular ultrasound have shown that progression of atherosclerotic plaque can be halted when LDL-C levels are reduced to below 70 mg/dl.22,23

PCSK9 is a serine protease that reduces LDLR levels. Inhibition of PCSK9 thus increases the number of LDLRs on the surface of hepatocytes. PCSK9i are monoclonal antibodies (mAbs) that bind to PCSK9, preventing it from binding to LDLRs, thereby reducing serum LDL-C levels (Figure 1).24,25

Figure 1.

Mechanism of action of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. In the hepatocyte, sterol regulatory element-binding protein 2 (SREBP-2) regulates the transcription of various lipids and proteins, including the low-density lipoprotein (LDL) receptor (LDLR) and PCSK9. In step 1, PCSK9 is processed in the endoplasmic reticulum (step 2), from where the mature form passes to the Golgi apparatus before being secreted (step 3). On the hepatocyte surface, the LDL receptor (LDLR) binds to circulating LDL cholesterol (LDL-C), and the resulting complex is internalized to the endosome (step 4). The LDLR then recirculates to the cell surface (step 5). This process occurs up to 150 times, increasing the quantity of LDL-C removed from the circulation. PCSK9 regulates the quantity of LDLRs on the hepatocyte surface by binding to the receptor, which is then internalized and degraded in the lysosome (steps 6 and 7), preventing LDLRs from being recycled to the cell surface.

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The gene for PCSK9 was identified around 15 years ago in the context of research into the phenotype of familial hypercholesterolemia (FH), which was soon shown to be associated with a gain-of-function mutation in this gene.26,27 The subsequent discovery of loss-of-function PCSK9 variants associated with lower serum LDL-C levels and reduced CV risk led to the development of the pharmacological model underlying PCSK9i.28 Anti-PCSK9 mAbs were soon developed and a series of clinical research programs were established to test the ability of PCSK9i to reduce CV events.29 At the same time, efforts continued to develop alternate ways of inhibiting PCSK9 (Table 1).30,31

Three mAbs have been developed as PCSK9i: alirocumab, bococizumab and evolocumab. They act by binding to PCSK9, preventing it from binding to LDLRs and being degraded in the lysosome, and thereby increasing the number of LDLRs (Figure 1).25 Alirocumab and evolocumab are fully human immunoglobulins (Ig) of the IgG1 and IgG2 isotypes, respectively, while bococizumab is a humanized IgG2. All are administered subcutaneously, and since they are complete antibodies their half-life is long (one injection every 2-4 weeks).

In general, anti-PCSK9 mAbs have been shown to be safe in cardiovascular outcomes trials (Table 5),11–13 confirming data from initial studies.36 Administration of these agents can result in local reactions such as erythema, swelling or itching, which are usually mild, the incidence of which ranges between 2.1% and 10.4% (Table 5). The highest incidence of such reactions was seen with bococizumab, which may be due to its partially murine origin.

No increase was seen in the incidence of new-onset diabetes (Table 5), contradicting the hypothesis that lower LDL-C levels could raise the risk of diabetes.62 This neutral effect on glycemic control was confirmed in a subanalysis of the FOURIER trial.63

No hepatic or muscular toxicity was observed. Neutralizing antidrug antibodies were detected in 43 patients (0.5%) in the alirocumab group in ODYSSEY OUTCOMES, but were not observed with evolocumab in FOURIER. As stated above, the frequent finding of neutralizing antidrug antibodies against bococizumab led to the discontinuation of its clinical development program. The most common adverse reactions to evolocumab were nasopharyngitis (4.8%), upper respiratory tract infection (3.2%), back pain (3.1%), arthralgia (2.2%), influenza (2.3%), and nausea (2.1%). The most common adverse reactions with alirocumab were local injection site reactions such as erythema, pain and hematoma.

Fears that very low LDL-C levels could be related to cognitive dysfunction have not so far been confirmed in clinical trials. In the EBBINGHAUS trial, which assessed neurocognitive function in detail in patients under evolocumab, no significant differences from placebo were seen at 24 weeks or at the end of the trial.64

Although the safety profile of anti-PCSK9 mAbs has been shown to be excellent in the medium term, the long-term effects of exposure to these agents are unknown. Genetic syndromes associated with FH, particularly those caused by loss-of-function mutations in the PCSK9 gene, may represent a model of prolonged exposure to PCSK9i.65 No neurocognitive disorders are reported in carriers of these mutations, except for one mutation in APOB (truncated isoform of ApoB29.4). However, the risk of hepatic steatosis is high (>70% in truncated isoforms of ApoB100).

Despite the efficacy of PCSK9i in reducing CV events, they have been used relatively little in clinical practice,66 mainly due to their high price. Cost-effectiveness analyses of the therapy are therefore essential, and several such studies have been published. The results have been highly variable, with incremental cost-effectiveness ratios ranging between 30 000 and 166 000 euros per quality-adjusted life year67 depending on the simulation model, the profile of patients included in the analysis, the context of use, and the cost of the treatment.

A ‘highest risk-highest benefit’ strategy has been proposed to improve the cost-effectiveness of these agents.68 In such a strategy, these agents should be used in patients at the highest risk, i.e. those with the greatest likelihood of suffering a CV event, such as those with a history of CVD and polyvascular disease or diabetes. Furthermore, assuming that relative risk reduction in patients at high CV risk is proportional to the absolute reduction in LDL-C, and that the magnitude of percent LDL-C reduction with PCSK9i therapy is similar across baseline LDL-C subgroups, patients with the highest starting LDL-C will achieve the greatest absolute reduction in LDL-C and hence the greatest relative risk reduction (highest benefit). On the basis of this concept, these guidelines propose that PCSK9i should preferentially be used in patients who are most likely to benefit from them, taking into consideration the patient's CV risk and absolute LDL-C level.

With regard to the cost-effectiveness of PCSK9i in Portugal, although precise figures are lacking, in December 2018 the Portuguese National Authority for Medicines and Health Products (INFARMED) published its Public Assessment Report on in-hospital use of evolocumab, which stated that “the incremental cost-effectiveness analysis of the introduction of evolocumab into the therapeutic arsenal, and the resulting impact on budgets, were considered acceptable.”69

Patients with established CVD, particularly those who have already suffered an atherothrombotic event, are at the highest risk for recurrent CV events.70 Given the association between LDL-C levels and risk of events, the therapeutic targets recommended in these patients are particularly strict, with the European guidelines recommending LDL-C levels <70 mg/dl,5 while recognizing that subgroups at extreme risk may benefit from even lower levels (<55 mg/dl).7

In these patients, the first-line therapy should be high-intensity statins (atorvastatin 40-80 mg or rosuvastatin 20-40 mg), together with dietary counseling and appropriate lifestyle changes. However, according to some published simulations, around 32% of patients will not attain target LDL-C levels solely with high-intensity statin therapy, and so other lipid-lowering agents will need to be added.71 The next step is to consider the addition of ezetimibe, a low-cost and well-tolerated drug, which will further reduce LDL-C levels,72 enabling a further 19% of patients to attain target levels. Even so, in around 14% of patients, LDL-C levels will remain above the target, and for these treatment with PCSK9i should be considered.

Rational use of these drugs entails identifying groups at the highest absolute risk and with the highest LDL-C levels, in whom the expected benefit is greatest. This is the approach recommended by most published guidelines on the use of PCSK9i (Table 6).

In 2016, the UK National Institute for Health and Care Excellence (NICE) guidelines on the use of PCSK9i in patients with established CVD set LDL-C thresholds of 150 mg/dl for patients at high risk (ACS, ischemic stroke, coronary or other arterial revascularization, coronary heart disease or peripheral arterial disease) and 130 mg/dl for those at very high risk (polyvascular disease or recurrent CV events). The only case in which PCSK9i were to be considered for primary prevention was in HeFH with LDL-C >190 mg/dl.73 The Spanish Society of Cardiology recommends these drugs for secondary prevention in patients with ischemic heart disease and LDL-C >100 mg/dl despite optimal lipid-lowering therapy, and in those with LDL-C >70 mg/dl and recurrent ACS or ischemic heart disease and FH.74 They are also recommended in patients with ischemic heart disease and demonstrated statin intolerance, as well as those without known CVD but with LDL-C >130 mg/dl and type 1 or 2 diabetes with target organ damage, estimated glomerular filtration rate <60 ml/min/1.73 m2, or SCORE >10%. The European Society of Cardiology/European Atherosclerosis Society (ESC/ESA) guidelines recommend PCSK9i in patients at very high CV risk with clinical or imaging evidence of atherosclerotic disease who, despite recommended maximally tolerated statin plus ezetimibe therapy, have LDL-C levels >140 mg/dl, and in those with rapidly progressive atherosclerotic CVD (defined as recurrent ACS, repeated unplanned coronary revascularizations, or recurrent ischemic stroke, within five years of the index event) and LDL-C levels >100 mg/dl.75

The American College of Cardiology/American Heart Association guideline on the management of blood cholesterol regarding addition of nonstatin therapy to statin therapy specifies that associating ezetimibe or a PCSK9i for secondary prevention should be considered in patients if the target LDL-C reduction of ≥50% has not been achieved (threshold of <70 mg/dl) under maximally tolerated statin therapy. For patients without comorbidities, the first step should be the addition of ezetimibe. However, in patients with a risk-enhancing factor (diabetes, chronic kidney disease, CV event under statin therapy, history of ischemic stroke or MI, age ≥65 years), a PCSK9i should be used instead of ezetimibe if the desired reduction in LDL-C is >25%.76 The more recent American guidelines on the management of hypercholesterolemia support optimizing initial therapy with ezetimibe before considering a PCSK9i, and add a further recommendation to assess the cost-effectiveness of these drugs, analysis of which shows that at 2018 prices in the US, they are “low value”.14 Such considerations, which do not question the results of the clinical trials but instead focus on health gains, will largely depend on the cost of PCSK9i in each country and the incremental cost-effectiveness ratios deemed acceptable within each health system.

After assessing the clinical evidence, cost-effectiveness analyses and the guidelines published by other medical societies, the authors of this document recommend associating a PCSK9i in patients under optimal lipid-lowering therapy who have already suffered an atherothrombotic event and also have:

LDL-C ≥140 mg/dl; or

LDL-C ≥100 mg/dl plus one of the following:

• –

  Diabetes with target organ damage such as proteinuria

• –

  Polyvascular disease

• –

  Significant multivessel coronary disease, with or without revascularization

• –

  Recurrent CV event within five years of the index event

• –

  FH.

Before considering introducing a PCSK9i, all the following conditions should be met:

• –

  Maximally tolerated high-intensity statin therapy (atorvastatin 40-80 mg or rosuvastatin 20-40 mg)

• –

  Addition of ezetimibe 10 mg

• –

  Adequate control of other risk factors

• –

  Implementation of lifestyle changes, including dietary counseling and smoking cessation (Figure 2).

  
  

  Figure 2.

  Treatment algorithm for lipid-lowering therapy in patients with a previous atherothrombotic event. CV: cardiovascular; FH: familial hypercholesterolemia; LDL-C: low-density lipoprotein cholesterol; PCSK9i: PCSK9 inhibitor; TOD: target organ damage.

  a In patients at very high CV risk (e.g. previous atherothrombotic event plus diabetes, polyvascular disease or recurrent CV event), target LDL-C level should be <55 mg/dl.

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Use of PCSK9 inhibitors in familial hypercholesterolemia without known cardiovascular disease

The ESC/EAS guidelines recommend the use of PCSK9i in patients with HeFH without established CVD but at high or very high CV risk if they have LDL-C >180 mg/dl on optimal lipid-lowering therapy.77 They also recommend that in the presence of additional risk factors – diabetes, high Lp(a) levels, premature CVD in a first-degree relative, smoking, and indicators of severity on imaging exams – the LDL-C threshold above which the use of PCSK9i should be considered should be lowered to 140 mg/dl (Figure 3).

Figure 3.

Treatment algorithm for lipid-lowering therapy in patients with familial hypercholesterolemia without known CVD. CV: cardiovascular; CVD: cardiovascular disease; LDL-C: low-density lipoprotein cholesterol; Lp(a): lipoprotein(a); PCSK9i: PCSK9 inhibitor; TOD: target organ damage.

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PCSK9i are recommended as additional therapy to reduce LDL-C levels in patients with HoFH whether or not they are also undergoing LDL apheresis. However, they are not recommended in patients with two receptor-negative alleles in the LDLR gene, in whom LDLR activity is less than 2%, since the mechanism of action of PCSK9i requires a certain level of LDLR activity.44,54

In patients with FH with no previous CV event, associating a PCSK9i should be considered if even after optimal lipid-lowering therapy they have:

LDL-C ≥180 mg/dl; or

LDL-C ≥140 mg/dl plus one of the following:

• –

  Diabetes with target organ damage such as proteinuria or one major risk factor

• –

  Lp(a) >50 mg/dl

• –

  Major risk factors such as uncontrolled stage 2 or 3 hypertension (blood pressure >160/100 mmHg)

• –

  Premature CVD in a first-degree relative (men aged <55 years; women aged <60 years)

• –

  Significant subclinical atherosclerotic disease.

Again, before considering introducing a PCSK9i, all the following conditions should be met:

• –

  Maximally tolerated high-intensity statin therapy (atorvastatin 40-80 mg or rosuvastatin 20-40 mg)

• –

  Addition of ezetimibe 10 mg

• –

  Adequate control of other risk factors

• –

  Implementation of lifestyle changes, including dietary counseling and smoking cessation.

In summary, the administration of PCSK9i should be considered for patients who are unable to tolerate appropriate doses of at least three statins, especially if additional risk factors are present such as FH, polyvascular or multivessel disease, or rapidly progressive atherosclerotic CVD.77

PCSK9i should only be prescribed in a hospital environment under the coordination of specialists in the management of CV risk. Consultations should be based on pre-established diagnostic and therapeutic protocols prepared by a multidisciplinary team.

Eligibility for PCSK9i therapy should be assessed after optimization of pharmacological therapy with maximally tolerated statin doses and ezetimibe, as well as optimization of non-pharmacological therapy, particularly diet guided by a nutritionist and control of other CV risk factors including smoking.6,77 Monitoring of PCSK9i therapy should include verification of adherence to maximally tolerated statins and ezetimibe; the patient's lipid profile should be reassessed after four weeks of full adherence if appropriate. Renal and liver function should be assessed before treatment begins.

Initiation of treatment with a PCSK9i is an opportunity to offer the patient a structured multidisciplinary educational program focusing on atherosclerotic disease and its treatment, using multimedia teaching materials.

The first administration of the drug should take place in hospital and the patient should be monitored for 30 min. Subsequent administrations can be performed at home when the patient or their carers have been duly instructed.

The lipid-lowering effect of the therapy should be assessed around four weeks after beginning treatment. Treatment discontinuation should be considered in poor responders (LDL-C reduction <25%), while dose reduction should be considered if LDL-C levels fall below <25 mg/dl.13

Monitoring of LDL-C levels should be performed at least every six months. Any adverse events should be reported to the National Pharmacovigilance System (Figure 4).

Figure 4.

Clinical management of patients under PCSK9 inhibitors.

a Can be adjusted to 150 mg.

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PCSK9i are a new therapeutic option that significantly reduces LDL-C levels and CV risk in patients already receiving optimal lipid-lowering therapy.

These guidelines for the use of PCSK9i in clinical practice in Portugal are the result of a multidisciplinary consensus that is centered on prioritizing their use in patients who will derive the greatest benefit: those with the highest risk and the highest LDL-C levels. As with all guidelines, their application in clinical practice cannot replace the clinical assessment of the individual patient.

RFC has received consulting or speaker fees from MSD, Bial and Amgen.

PMS has received consulting or speaker fees from Bayer, JABA Recordati, MSD Portugal, Kowa Pharmaceuticals, Novartis, Daiichi Sankyo, Amgen, Sanofi-Regeneron and Tecnimede.

FA reports no conflicts of interest.

CG has received consulting or speaker fees from MSD and Amgen.

JF has received consulting fees from Amgen.

JM has received consulting or speaker fees from Astra Zeneca, Amgen, Bayer, Boehringer Ingelheim, Jaba, Servier, and Novartis.