FormalPara Key Points

PCSK9-targeted therapy demonstrates effectiveness and safety in reducing LDL-C levels, making it a valuable option for high-risk patients with atherosclerotic cardiovascular disease.

The balanced adverse event profile, positive effects on plaque burden, and anticipated user-friendly formulations hold promise for wider accessibility in the global fight against atherosclerosis cardiovascular disease.

1 Introduction

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality and morbidity worldwide. Hypercholesterolemia is a major and causal risk factor for ASCVD [1]. Lowering LDL-C is therefore an established and effective pharmacological approach to reduce the risk of ASCVD. The use of lipid-lowering therapies has led to a significant reduction in the occurrence of major adverse cardiovascular events (MACE), making them a fundamental pillar in current preventive treatment [2]. The expected benefit for reducing ASCVD risk is correlated to the magnitude of LDL-C reduction [3]. This emphasizes the importance of initiation of potent LDL-C-lowering therapies combined with good medication adherence. The latter is often compromised by adverse effects attributed to lipid lowering treatment (mostly in statin users), and loss of adherence is more common in female patients and in those with a low socioeconomic status [4]. Real-world studies have reported that after 2 years, only 50% of patients continue statin therapy [5, 6], resulting in a significant residual ASCVD risk [6,7,8].

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a relatively new target to lower LDL-C. Pharmacological reduction of circulating PCSK9 enhances the clearance of LDL-C from circulation through LDL receptor-mediated mechanisms [9]. At present, evolocumab and alirocumab, fully humanized monoclonal antibodies (mAbs) targeting PCSK9, as well as inclisiran, a synthetic small interfering RNA (siRNA) which inhibits translation of PCSK9 mRNA, have been approved for clinical use as injectable lipid lowering therapies (LLT). PCSK9-targeted therapy is recommended by the European (ESC/EAS) and American (ACC/AHA) guidelines as additional lipid-lowering agents in adult patients with familial hypercholesterolemia (FH) or established ASCVD requiring additional LDL-C lowering to reduce the risk of myocardial infarction, stroke, and coronary revascularization [10,11,12].

Monoclonal antibodies directed against PCSK9 have been shown to reduce the risk of recurrent cardiovascular events in patients who were on statin therapy [13, 14]. Also, among patients with coronary artery disease, the addition of PCSK9-targeted therapy to high-intensity statin therapy resulted in significant coronary plaque regression [15, 16]. However, there are conflicting secondary reports about the long-term tolerability of these efficacious agents [17, 18]. This review presents and discusses the current clinical and scientific evidence regarding the long-term efficacy and tolerability of PCSK9-targeted therapy.

2 Lipid Metabolism and PCSK9-Targeted Therapy

LDL receptors (LDLR) on the surface of liver hepatocytes primarily control plasma LDL-C levels and are responsible for eliminating approximately 70% of circulating LDL-C particles [19]. PCSK9 is a proteolytic enzyme produced mainly in the liver and a major regulator of LDL-C metabolism [20]. Circulating PCSK9 binds the LDLR, leading to endocytosis of the LDLR–PCSK9 complex into the hepatocyte and ensuing degradation of the LDLR in lysosomes [20]. Premature degradation of the LDLR leads to fewer LDLRs present on the cell surface, which invariably gives rise to increased serum LDL-C levels [9, 21]. In Fig. 1, an overview of existing PCSK9-targeted therapies is provided along with their respective mechanisms of action, which are further described below.

Fig. 1
figure 1

Mechanism of action of current PCSK9 targeted therapy: evolocumab, alirocumab and inclisiran

Full size image

Alirocumab and evolocumab are fully humanized monoclonal antibodies that specifically bind PCSK9, resulting in an increased recycling of LDLR, accelerated clearance of LDL-C particles, and, thereby, lower levels of circulating LDL-C [21, 22]. Alirocumab and evolocumab are administered by a subcutaneous injection once every 2 weeks or once a month. This subcutaneous injection introduces an excess of antibodies that capture all free plasma PCSK9 [9]. Together, evolocumab and alirocumab are hereafter referred to as PCSK9 mAbs.

Inclisiran is a long-acting synthetic small-interfering RNA (siRNA) directed against the mRNA encoding the PCSK9 protein. Targeting PCSK9-mRNA in the liver reduces intracellular and extracellular PCSK9 concentrations, leading to a significant LDL-C reduction [23, 24]. Its effect lasts longer than other lipid lowering agents, which translates into a dosing scheme of only two injections per year.

3 Pharmacological Efficacy

3.1 Lipid Levels

The potent lipid-lowering efficacy of evolocumab [25,26,27,28] and alirocumab [29,30,31,32] was shown in many clinical trials with reductions in LDL-C levels by at least 60% when used in combination with statins and 50–60% when used as monotherapy. Inclisiran has been shown to reduce mean PCSK9 plasma protein levels by 70% and LDL-C levels by up to 56% [24, 33, 34]. The results of plasma LDL-C lowering remained consistent across various high-risk clinical subgroups (such as patients at high ASCVD risk, patients with statin intolerance, and patients with FH) and independent of baseline plasma PCSK9 levels [35, 36]. PCSK9-targeted therapy was also shown to be highly effective in patients with FH or statin-intolerant patients, representing an important therapeutic option for these high-risk patients [26, 37, 38]. Moreover, PCSK9-targeted therapy lowers apolipoprotein B levels and non-HDL cholesterol, both important markers of ASCVD risk [39]. Unlike statins, evolocumab and alirocumab also reduce lipoprotein(a) levels by up to 25%. However, the molecular mechanism underlying this effect has not yet been fully elucidated [40, 41]. Interestingly, in a recent meta-analysis concerning statins, a significant reduction in high-sensitive CRP (hs-CRP) levels was observed among patients with ASCVD, with a reduction of −0.97 mg/L [95% confidence interval (CI): − 1.26, − 0.68 mg/L; P < 0.001), whereas a meta-analysis on PCSK9-targeted therapy did not show a reduction (weighted mean difference: 0.002 mg/L, CI: – 0.017, 0.021; P = 0.807; I2 = 37.26%) in hs-CRP levels compared with the placebo, irrespective of the type of drug, dosing frequency, changes in LDL-C levels, or cumulative dosage [42, 43]. The difference between PCSK9-targeted therapy and statins on hs-CRP raises the question to what extent attenuation of inflammation drives cardiovascular disease reduction for both agents. However, it should be mentioned that most PCSK9-targeted therapy trials were performed in patients that were already using statins, making it hard to untangle any fundamental differences.

3.2 Atherosclerotic Disease

PCSK9-targeted therapy offers the prospect of positive effects on atherosclerotic plaque burden and plaque characteristics (Table 1). The association between serum PCSK9 levels and the extent of atherosclerotic plaque burden has been assessed in a number of imaging studies. Elevated PCSK9 levels are independently associated with coronary artery calcification (CAC) [44], the fraction and amount of necrotic core tissue in coronary atherosclerosis [45], and overall atherosclerotic extent as measured by intima media thickness or total plaque volume [46,47,12]. However, there is a large discrepancy between recommended treatment as studied in clinical trials and real-world treatment data with regards to LDL-C target achievement. In less controlled real-world settings, these objectives are often unattained as a result of clinical inertia exhibited by healthcare providers and poor patient adherence [90, 91]. The sustained utilization of PCSK9-targeted therapy has been shown to be promising, with 92% to 98% of patients still using PCSK9-targeted therapy after 1 to 2 years after initiation of therapy [92,93,94,95,96]. The extent of adherence to PCSK9-targeted therapy is relatively under-investigated, with one single country, multicenter, observational retrospective study reporting 95.2% adherence, defined as medication adherence ratio > 80% among 798 patients after up to 18 months [96]. In addition, only a very small proportion of patients discontinue PCSK9-targeted therapy due to adverse drug reactions [9]. While long-term follow-up studies on inclisiran adherence (e.g., NCT05399992) are still ongoing, the convenience of its biannual administration schedule is expected to significantly enhance treatment adherence, potentially leading to improved clinical outcomes in a substantial population of high-risk patients [97]. In conclusion, PCSK9-targeted therapy is very effective and well tolerated in routine clinical practice, leading to high adherence. This will result in more patients achieving their recommended LDL-C targets and decrease the global burden of ASCVD.

6 Conclusions

PCSK9-targeted therapy is effective and well tolerated. The number of adverse events in RCTs are well balanced between patients receiving PCSK9 lowering agents and placebo, which justifies the statement that PCSK9-targeted therapies are safe. While there is compelling evidence that further lowering LDL-C reduces the risk of ASCVD, achieving recommended LDL-C targets remains challenging. Despite the use of statins, many high-risk patients do not achieve sufficient LDL-C reduction and remain at elevated ASCVD risk. PCSK9-targeted therapy offer potent LDL-C reduction potential for high-risk patients, with documented positive effects on plaque burden and characteristics. In general, there is no heightened incidence of adverse events of particular interest, including diabetes, neurocognitive effects, and vitamin deficiency, observed among patients undergoing PCSK9-targeted therapy. Anticipated advancements in user-friendly formulations (e.g., oral pills or one-time gene editing) [98] and also the emergence of new subcutaneous PCSK9-targeted therapies such as lerodalcibep and recaticimab [99], alongside forthcoming long-term clinical studies, are expected to confirm its favorable efficacy and safety profile. Hopefully, PCSK9-targeted therapy will become more accessible worldwide in the fight against atherosclerotic cardiovascular disease.