PCSK9 inhibition: from effectiveness to cost-effectiveness

Dyslipidaemia is a complex disorder characterised by abnormal lipid levels in the blood, including cholesterol and triglycerides, and plays an important role in the development of atherosclerotic cardiovascular disease. Most risk factors for cardiovascular disease are modifiable, and dyslipidaemia is a key factor among them. It can result from a combination of genetic and environmental factors. A distinction is made between primary dyslipidaemia, which is mainly caused by inherited genetic changes, and secondary dyslipidaemia, which is due to underlying diseases or certain medications. The treatment of dyslipidaemia has evolved over the years. In the past, statins were the first choice, but newer drugs, such as proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, have gained prominence due to their effectiveness in lowering lipids. Although recent guidelines recommend PCSK9 inhibitors for high-risk patients and patients who cannot tolerate statins, their widespread use is limited because of cost. Several meta-analyses have confirmed the efficacy and safety of PCSK9 inhibitors and have shown a significant reduction in low-density lipoprotein (LDL) cholesterol levels. However, the long-term side effects and interactions with other risk factors for cardiovascular disease remain uncertain. In addition, cost-effectiveness analyses have shown mixed results, with some countries considering PCSK9 inhibitors to be cost-effective for certain patient groups, while others consider them less economical. Meanwhile, initial data from patients using PCSK9 inhibitors support the results of the clinical trials. To summarise, PCSK9 inhibitors represent a revolutionary solution for lowering LDL cholesterol, but their cost-effectiveness remains controversial. Despite the controversy, they offer clear benefits for high-risk patients and should therefore be considered in the treatment of dyslipidaemia.


Introduction
Dyslipidaemia is a heterogeneous disorder characterised by abnormal lipid levels in the blood.These disorders are characterised by changes in the quantity, quality, or both of various lipid components, including cholesterol and triglycerides (1).They play an important role in the development of atherosclerotic cardiovascular diseases (CVD), such as coronary heart disease, acute myocardial infarction (MI), ischaemic stroke, peripheral arterial disease, and heart failure.The vast majority of risk factors for CVD are modifiable risk factors, such as diabetes mellitus, smoking, hypertension, obesity, and physical inactivity, with dyslipidaemia being one of the most important (2).Dyslipidaemia can result from a combination of genetic and environmental factors.A distinction is usually made between primary and secondary dyslipidaemia.Primary dyslipidaemia, of which familial hypercholesterolaemia is the most important and common, refers to lipid disorders that are primarily caused by inherited genetic changes.Traditionally, they are categorised into types I-V according to Frederickson's classification, based on the particles that show elevated levels in the blood.However, Frederickson's classification was first published in the 1960s.Today, patients in the 21st century need modern and updated classifications based on all aspects of cardiovascular risk and not just elevated lipid particles in the blood (3).Secondary dyslipidaemia or acquired dyslipidaemia occurs due to underlying diseases, lifestyle factors, or the use of certain medications.The most important risk factors for the development of secondary dyslipidaemia are obesity, diabetes mellitus, chronic kidney disease, chronic liver disease, and certain medications such as corticosteroids and diuretics taken over a long period of time (4).Even the new checkpoint inhibitors for oncological treatment have been observed to increase cholesterol levels, as indicated in the summary of product characteristics.Dyslipidaemia is therefore an increasingly attractive topic for the medical community, especially with the development of new therapeutic approaches (5).Until relatively recently, treatment with statins was the first choice for the treatment of dyslipidaemia.Nowadays, new drugs are being developed.The first new drug to come on the market was ezetimibe, which binds to the NPC1L1 transporter protein and thus inhibits fat absorption in the intestine (5).Proprotein convertase subtilisinkexin type 9 (PCSK9) inhibitors were also developed: alirocumab and evolocumab as monoclonal antibodies, followed by the small RNA-interfering molecule inclisiran (6).All of these agents inhibit PCSK9, prolong low-density lipoprotein (LDL) receptor activation and lower LDL cholesterol levels (6).
In view of these therapeutic approaches, the European Atherosclerosis Society has published guidelines for the treatment of dyslipidaemia.The latest edition is from 2019 and the major innovation in these guidelines is the stratification of CVD risk for patients with primary dyslipidaemia using the revised SCORE system, called SCORE2 and SCORE-OP (7).In addition, these guidelines have revised the nomenclature of statin intolerance and place a strong emphasis on increasing statin treatment in patients previously discontinued due to non-specific, possibly statin-related symptoms.However, an important addition to the guidelines was also the inclusion of treatment recommendations based on new studies of PCSK9 inhibition that demonstrate the efficacy and safety profile of these drugs (8).
Although recent guidelines recommend their use in patients with a very high cardiovascular risk and in patients who cannot tolerate statins (which is not uncommon), PCSK9 inhibitors are not as widely used as statin treatment because of their cost (9).The aim of this review was to present the results of several meta-analyses conducted in the field of dyslipidaemia over the last 5 years, with a focus on PCSK9 inhibition.Another important aim of this paper was to discuss the results of the various studies in which PCSK9 inhibitors have been analysed in the context of cost-effectiveness with other lipid-lowering (LL) drugs.Instead of the 5-year period used for the aforementioned meta-analyses on safety and efficacy, we have chosen a shorter 3-year period (2020-2023) to get the best possible overview of the current market situation.

Methods
For this literature review, PubMed, Scopus, Embase, and Web of Science were searched between October 2022 and 5 May 2023 using the keywords "PCSK9 inhibitors", "efficacy", "safety" and "cost-effectiveness".We considered articles published in the 5-year period before the search.After a thorough assessment by two independent reviewers, we included 30 publications focusing on the efficacy and cost-effectiveness of PCSK9 inhibitors in the treatment of dyslipidaemia.

Safety and efficacy of PCSK9 inhibitor treatment
PCSK9 inhibitors significantly reduced cardiovascular events, heart attacks, and ischaemic strokes compared to statins (Table 1).However, these consistent benefits were not observed when compared with ezetimibe (10,11).Alirocumab and evolocumab showed a reduction in cardiovascular disease, myocardial infarction, and stroke compared to placebo, with varying effects on mortality (15,20,21).PCSK9 inhibitors showed a greater reduction in LDL-C levels compared to ezetimibe, with no significant differences between doses (14-16).The risk of myocardial infarction, stroke, heart failure, diabetes mellitus, neurocognitive events, and death was comparable to placebo in both lipid-lowering trials and clinical outcome trials (17,18).The combination of dual lipid-lowering therapy with PCSK9 inhibitors and ezetimibe led to a significant reduction in total atheroma volume (12).PCSK9 inhibitors did not increase the risk of diabetes or cataracts (13,25,30,31).In the FOURIER study, evolocumab showed a 31% relative risk reduction in venous thromboembolism compared to placebo.The expected relative risks for cholesterol reduction with PCSK9 inhibitors were reported as 0.851, 0.810, and 0.770 for a 20%, 30%, and 40% reduction, respectively (28).Lowering LDL-C levels was associated with a lower risk of major cardiovascular events, myocardial infarction, stroke, and death overall across different interventions and subgroups (27).
The analysis showed no significant difference in overall or serious adverse events compared to the control group.Alirocumab showed superiority in reducing serious adverse events and had fewer diabetes-related events than the control (Continued) group (21,26).No significant differences were observed for evolocumab (22).There was also no significant difference in neurocognitive and neurological adverse events (23).The odds ratios for myalgia and myocardial infarction did not reach statistical significance.Both evolocumab and alirocumab had a favourable effect on total atheroma volume (24).PCSK9 inhibitors significantly reduced LDL-C levels and had a favourable effect on lipid profiles (19, 29).There was no evidence of new-onset diabetes, flu-like symptoms, or other adverse events leading to discontinuation of treatment (13).PCSK9 inhibitors did not increase the risk of injection site reactions over a 5-year period (13).

Discussion
Drugs for the treatment of dyslipidaemia are among the most commonly used medicines.According to the National Ambulatory Medical Care Survey published by the Centres for Disease Control and Prevention in 2019, medications to treat dyslipidaemia were the second most frequently mentioned medications in primary care practices in the United States, surpassed only by analgesics, while atorvastatin was the second most frequently used prescription medication (40).For decades, statins were synonymous with the treatment of dyslipidaemia, but in recent years the new generation of lipid-lowering drugs has become more widely used as a result of new research findings and general awareness of the potential adverse effects of statins (although these are usually vastly overestimated).In second place in the treatment of dyslipidaemia are currently the PCSK9 inhibitors-alirocumab, evolocumab, and inclisiran, which is not strictly a PCSK9 inhibitor, but is often included in the same group of drugs.Numerous research papers have been published on the safety and efficacy of PCSK9 monoclonal antibodies, and all these papers have in common that they have demonstrated the efficacy in lipid lowering and the good safety profile of these drugs (41).Another important point that is often emphasised as a major advantage is their compliance, as they are administered once or twice a month.However, to date, no study has been published that demonstrates better compliance compared to standard daily oral statin treatment or combined treatment with statin + ezetimibe or bempedoic acid (42).In addition, recent results have confirmed the efficacy of PCSK9 inhibitors in reducing major cardiovascular events and have also shown the benefit of treatment with PCSK9 inhibitors in schematic stroke (43).Regarding the safety profile of PCSK9 inhibitors, most studies showed a very good safety profile; however, the targets were evaluated in the relatively short term so that potential long-term adverse effects could not yet be assessed.This brings us to the main problem in interpreting the  Our patients not only have dyslipidaemia, but very often other risk factors that lead to serious cardiovascular events as well.One positive effect of the 21st century is the willingness of the medical community to publish real-world data on certain topics, and PCSK9 inhibition is no exception.There is an increasing number of publications based solely on real-world data confirming the results of clinical trials and meta-analyses of PCSK9 inhibitors (45-48).
An important issue that has not yet been mentioned is the costeffectiveness of PCSK9 inhibitors.An important factor in treatment with PCSK9 inhibitors is their relatively high cost.The initial cost-benefit analyses all agreed that PCSK9 inhibitor therapy is not cost-effective, with reports ranging from developed countries to developing countries (49)(50)(51).Nevertheless, the price of evolocumab and alirocumab has fallen in recent years (52).However, even with this price reduction, some cost-effectiveness analyses have not shown positive results for the general use of PCSK9 inhibition.One of the most recent published analyses from the UK showed quality-adjusted life years (QALY) of 0.53 and 0.86 for evolocumab and alirocumab, respectively, at a cost of approximately £45,000.With a National Health Service willingness to pay £30,000/QALY, PCSK9 inhibitors do not appear to be cost-effective (33,53).On the other hand, a Swedish analysis showed that PCSK9 inhibitors are cost-effective in the secondary prevention of myocardial infarction in combination therapy for very high-risk patients (54).

Conclusion
When we talk about PCSK9 inhibitors, we must all agree that they represent a revolutionary solution for lowering LDL cholesterol that the medical community awaited for decades after the introduction of statins.Finally, we now have clinical trial results and real-world data confirming the efficacy of the treatment regimen and the safety profile of evolocumab and alirocumab.For other novel treatment options based on PCSK9 inhibition, studies demonstrating the potential cardiovascular benefit or real-world data are still lacking.It must be mentioned that these new drugs are also expensive.When we talk about the costs and expenses of evolocumab and alirocumab, we can safely say that the cost-effectiveness of PSCK9 inhibitors is still very controversial, and the interpretation of the analysis results depends on the thresholds of the statutory health insurance funds.However, their benefit in high-risk patients is absolutely clear, regardless of the costs.

TABLE 2
Cost-effectiveness of the PCSK9 inhibitor treatment.