PCSK9 inhibitors: when statins aren’t enough

The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab and alirocumab, are novel lipid-lowering agents that can produce a further substantial reduction in LDL cholesterol in patients who cannot reach target using standard therapy with statins and ezetimibe. This article examines the current approaches to lipid-lowering for primary and secondary prevention of cardiovascular disease and the place of these new agents in therapy.

Higher blood levels of LDL cholesterol mean higher rates of coronary heart disease, for different populations and at various concentrations of LDL cholesterol.1 For example, LDL cholesterol concentrations typically exceed 13mmol/L in individuals with homozygous familial hypercholesterolaemia and they can develop coronary events by their 20s or 30s.2 In people with heterozygous hypercholesterolaemia, LDL cholesterol can be above 8mmol/L and coronary events occur in the mid-50s.3

Since the launch of the statins in the mid-1990s, and in particular the introduction of the government’s National Service Framework for Coronary Heart Disease in 2000, lipid-lowering has been an integral and very successful component of pharmacological strategies to reduce cardiovascular risk. Between 1961 and 2012, the proportion of deaths in the UK caused by cardiovascular disease fell from 50% to 28%.4,5 Many factors have contributed – less smoking, treatment for hypertension and diabetes, antiplatelet therapy, increased physical activity – but, with about 80% of people with atherosclerotic disease now prescribed a statin6 and nearly 68 million prescriptions dispensed in 2016 in England alone,7 these drugs are likely to have played a big part. The statins are more effective than any of the cholesterol-lowering drugs preceding them: intensive statin therapy can halve LDL cholesterol levels by up to 2mmol/L (about half the population have a level of about 4mmol/L).1 Randomised controlled trials have shown that each 1mmol/L reduction in LDL cholesterol with a statin reduces the rate of major vascular events by about a quarter annually from the second year of treatment. A 2mmol/L reduction in LDL cholesterol for five years in 10,000 patients would prevent major vascular events in an estimated 1000 patients with pre-existing vascular disease (as secondary prevention) and in 500 people at increased risk as primary prevention.1

Beyond statins

Not all statins were created equal. Pravastatin and fluvastatin offer a relatively modest reduction in LDL cholesterol, inferior to that of simvastatin and well below the high-potency atorvastatin and rosuvastatin (see Figure 1).8 For some time, when high-potency statins were available only as branded products and were priced accordingly, management guidance recommended simvastatin – first at a ‘standard’ dosage (20–40mg daily) then at a high dosage (80mg daily). Following the expiry of patent protection for Lipitor (atorvastatin) in 2011, the tables turned: atorvastatin prescribing has been growing by 20% annually and it is now set to surpass simvastatin as the most frequently prescribed statin.9

Figure 1. Percentage reduction in serum LDL cholesterol according to daily dose of statin in clinical trials8

So, as resources allowed, the approach to lipid-lowering therapy has become more aggressive. NICE now recommends initiating atorvastatin at a dosage of 80mg daily for secondary prevention of cardiovascular disease, provided the risk of drug interactions and adverse effects is acceptable, and subject to patient preference.10 (The recommended dosage for primary prevention is 20mg daily.) The aim is to reduce non-HDL cholesterol by 40%. The strategy is similar for people with familial hypercholesterolaemia, with the aim of reducing LDL cholesterol by 50%.11

Evidently, even high-intensity statins are not sufficient in some cases. There is variability between patients in the reduction of LDL cholesterol achieved12 and, in clinical practice, many do not achieve the desired level.13 Why should statin monotherapy not deliver an adequate reduction in LDL cholesterol? Very high cholesterol levels, as may occur in people with familial hypercholesterolaemia, will still be high even after a 50% reduction. Adding ezetimibe, which exerts a complementary mechanism of action by inhibiting intestinal absorption of cholesterol, increases the proportion of patients achieving the target LDL cholesterol reduction but, even with this strategy, the reduction in LDL cholesterol is less than hoped for in about 20% of patients.14

Adverse effects and adherence

Some people can’t take statins, and some people won’t. The tolerability of statins became a controversial topic when, in 2014, NICE recommended atorvastatin for primary prevention in people with a =10% 10-year risk of developing cardiovascular disease.10 The balance of risks and benefits was undisputed for secondary prevention but a review of clinical trial data concluded that it was unfavourable for primary prevention.15

This raised the profile of the adverse effects of statins, prompting a detailed rebuttal by advocates of wider use.1 This response, which for the moment is the last and most comprehensive word on the subject, concluded that there is convincing evidence only that statins increase the risk of myopathy (by five cases per 10,000 patients treated for five years), diabetes (by 50–100 cases) and haemorrhagic stroke (by 5–10 cases). The absolute excess of adverse events associated with statins is about 1%–2%, it added, and there is “good evidence” that they do not cause symptomatic effects such as muscle pain and weakness (known as “statin intolerance”). How well the safety findings of clinical trials in populations selected for lower morbidity translate to clinical practice is a moot point and a different analysis put the risk of adverse effects of all severities at 18%.15 In the USA, the National Lipid Association Statin Safety Task Force concluded:16

“The clinician should acknowledge that statin intolerance is a real phenomenon, manifesting mostly as an array of muscle-related symptoms that include aching, stiffness, proximal motor weakness, fatigue, and back pain. Estimates of the frequency of muscle symptoms verifiably related to statin use range from 1% to 10%. Severe myopathy with objective weakness and/or markedly elevated muscle enzymes is rare. Reliable research designs are only beginning to address the actual frequency of statin muscle intolerance in populations.”

However, investigators from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) recently implied that statin intolerance is less than real: their analysis of adverse events (AE) reported in the trial showed “an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded… most AEs associated with statins are not causally related to use of the drug…”17

The concept of statin intolerance is now established in the public consciousness and in regulatory decision-making (it is a licensed indication for some alternative lipid-lowering agents). Adverse effects are cited as a major factor behind low adherence to statin therapy,18 estimates of which range from 40% to 80% of days covered by prescribed medication.19-22 Observational studies consistently report increased cardiovascular disease and mortality associated with low adherence23 showing that, whatever the rights and wrongs regarding the evidence, the consequences are real.

PCSK9 inhibitors – a new kind of lipid-lowering agent

The lipid-lowering effect of statins is mediated by an increase in the expression of the LDL receptor in the liver (following inhibition of cholesterol synthesis), thus enhancing the uptake of LDL cholesterol from the circulation and its subsequent catabolism. This is, in fact, the common final pathway by which other lipid-lowering agents act, and the reduction in cardiovascular risk associated with different agents correlates with the extent to which they consequently reduce LDL cholesterol.24 The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reach this common point via a new mechanism.

The enzyme PCSK9 binds to LDL receptors and promotes their degradation by hepatocytes, which has the effect of raising LDL cholesterol. Gene mutations that increase PCSK9 function occur in some individuals with familial hypercholesterolaemia; conversely, mutations that decrease PCSK9 function are associated with low levels of LDL cholesterol.25 PCSK9 inhibitors prevent the formation of the enzyme-receptor complex, preserving LDL receptors and thereby increasing hepatic LDL uptake from the circulation. They also increase levels of favourable HDL cholesterol in the circulation.

Two PCSK9 inhibitors were introduced in the UK in 2016 as adjuncts in lipid-lowering therapy. Evolocumab (Repatha) and alirocumab (Praluent) are monoclonal antibodies that bind to PCSK9, producing a profound reduction in circulating LDL cholesterol (see Figure 2).26 Both are licensed for use in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia as an adjunct to diet. They can be used in combination with a statin (alone or with other lipid-lowering agents) in patients who cannot achieve the required reduction in LDL cholesterol at the maximum tolerated dose of a statin; or alone or in combination with other lipid-lowering therapies in patients who are statin intolerant, or for whom a statin is contraindicated. Evolocumab is also licensed for use, in combination with other lipid-lowering agents, in adults and young people over 12 years with homozygous familial hypercholesterolaemia.

Figure 2. Percentage change from baseline (%CFB) in LDL cholesterol (LDL-C) during 12 weeks’ treatment with evolocumab in addition to statin/ezetimibe in patients with primary hyperlipidaemia or mixed dyslipidaemia26

Dosage and administration

Both PCSK9 inhibitors are administered by subcutaneous injection but the dose regimens for primary hypercholesterolaemia are slightly different. The initial dosage of evolocumab is 140mg every two weeks or 420mg monthly (the dosages are clinically equivalent, see Figure 2). Alirocumab is usually initiated at a dosage of 75mg every two weeks but a higher dosage of 150mg every two weeks (or 300mg every month) can be used if a greater initial reduction in LDL cholesterol is required. For patients with homozygous familial hypercholesterolaemia, the initial dosage of evolocumab is 420mg monthly, increased after 12 weeks if necessary to 420mg every two weeks.

Both PCSK9 inhibitors have been marketed in prefilled single-use pens. A 300mg dose of alirocumab requires the use of two pens; the evolocumab SureClick pen contains 140mg and three pens are needed for the 420mg dose (or a 420mg cartridge is also available).

No dose adjustment is recommended for older people (though experience in the over-75s is limited) or in patients with mild or moderate renal impairment or mild hepatic impairment. Evolocumab should be monitored closely in patients with moderate hepatic impairment because total exposure is lower and the effect on LDL cholesterol levels may be reduced. There is little experience with either drug in patients with severe renal or hepatic impairment.

Clinical use

NICE has recommended evolocumab and alirocumab as options for treating primary hypercholesterolaemia or mixed dyslipidaemia when LDL cholesterol is persistently above specified thresholds (see Table 1) after maximal tolerated lipid-lowering therapy.27,28 This is conditional on price discounting via confidential patient access agreements. The recommendation for evolocumab is limited to the fortnightly 140mg dose. Evolocumab has not been appraised for homozygous familial hypercholesterolaemia.

Table 1. NICE LDL cholesterol thresholds for treatment with the PCSK9 inhibitors evolocumab and alirocumab27,28

NICE based its conclusions on clinical trials showing that these agents significantly reduced LDL cholesterol levels when added to statin monotherapy (by 60%–70%) or a statin/ezetimibe combination (by 30%–40%) in studies lasting six months to one year. These effects are sustained during long-term use for up to three years (see Figure 3).29 In one recently published study in patients with atherosclerotic heart disease and LDL cholesterol levels =1.8mmol/L, evolocumab lowered LDL cholesterol by 59% to a median of 0.78mmol/L and reduced the risk of cardiovascular events (cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina or coronary revascularisation) by 15% after two years.30

Figure 3. Mean % change in LDL cholesterol from baseline, during long-term treatment with alirocumab when added to statin±ezetimibe therapy in patients with heterozygous familial hypercholesterolaemia29

In clinical practice, both PCSK9 inhibitors are likely to be prescribed as add-on therapy to statins and ezetimibe for people who are at a high risk of cardiovascular disease. NICE concluded that the large reduction in LDL cholesterol would probably offer a substantial benefit but it acknowledged uncertainty about the long-term effectiveness of PCSK9 inhibitors because of the theoretical risk that neutralising antibodies may develop. In clinical trials, neutralising antibodies were identified in 0.1%–0.4% of patients but this did not reduce the efficacy of treatment.

In a resource impact report, NICE estimates (based on data provided by alirocumab manufacturer Sanofi) that 8% of people with non-familial hypercholesterolaemia and 14% of those with the familial form do not have adequate control of LDL cholesterol with statins and ezetimibe and are thus eligible for treatment with alirocumab or evolocumab.31 The number of people likely to be treated with alirocumab or evolocumab in the current financial year is 4500 and this is estimated to rise to almost 14,000 by 2020/21. NICE does not estimate the cost impact because it won’t reveal the confidential discount but the basic NHS cost of a year’s treatment with each agent is about £4400. Against this, there are likely to be savings by reducing the number of patients with severe hypercholesterolaemia and coronary heart disease who need lipoprotein apheresis. NICE did not consider monotherapy with a PCSK9 inhibitor and it is likely the expense compared with a statin/ezetimibe will make this a rare choice for prescribers.

Adverse effects

A meta-analysis of 25 trials of evolocumab or alirocumab involving a total of 12,200 patients found that the overall rate of treatment-emergent adverse events was similar to that reported with ezetimibe and placebo over 12–52 weeks (50%–70%) and rates of specific adverse events were not statistically significantly different.32 The most frequently reported events were musculoskeletal disorders (10%–17% of patients), including back pain, arthralgia, muscle spasms and myalgia, nasopharyngitis and gastrointestinal disorders. Injection-site reactions were reported by about 2% of patients using evolocumab (vs 2% with placebo) and about 6% with alirocumab (vs 4% with placebo). Prescribing information for alirocumab states that most injection site reactions were transient and of mild intensity, resulting in discontinuation in 0.2% of patients (vs 0.3% in controls).33

Overall, the frequency of discontinuation due to adverse events in clinical trials was 1.9% with evolocumab (vs 2.3% with controls); in the case of alirocumab, it was 5.3% vs 5.1% with placebo and 8.8% vs 9.7% with ezetimibe.26,34


Reducing LDL cholesterol is crucial to lowering the risk of cardiovascular events and for most people, lifestyle change, statins and ezetimibe are effective. However, about one in 12 patients with non-familial hypercholesterolaemia, and one in seven of those with familial hypercholesterolaemia, do not reach the desired reduction in LDL cholesterol with this approach. NICE has recommended a new treatment step with the addition of evolocumab or alirocumab, both of which offer a further substantial reduction in LDL cholesterol and, on the basis of current evidence, good tolerability. The additional cost to the NHS is being withheld but, on the basis of the standard price of each agent, it is likely to be high.

Declaration of interests

None to declare.

Steve Chaplin is a medical writer specialising in therapeutics


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PCSK9 inhibitors: when statins aren’t enough

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