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Abstract

As a novel class of lipid-lowering agents, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors specifically block the binding of PCSK9 to low-density lipoprotein (LDL) receptors, inhibit the degradation of LDL receptors, and enhance the hepatic uptake and metabolism of circulating LDL-C, thereby exerting potent lipid-lowering effects.

For patients with ischemic stroke (IS) complicated by dyslipidemia, especially those at extremely high risk who fail to achieve lipid targets with statin monotherapy or statin combined with ezetimibe, as well as statin-intolerant individuals,PCSK9 inhibitors offer a new therapeutic option.

This article systematically elaborates on the mechanism of action and clinical efficacy characteristics of PCSK9 inhibitors, and comprehensively discusses their clinical application strategies, safety profiles and long-term benefits in different subgroups of IS patients with dyslipidemia. It also summarizes the latest research advances and future application prospects, aiming to provide a reference for clinicians to optimize lipid-lowering regimens and implement precise prevention and treatment strategies.

Keywords

Ischemic stroke; Dyslipidemia; PCSK9 inhibitors; Lipid-lowering therapy; Extremely high-risk population; Drug safety

1、Introduction

Patients at extremely high risk of ischemic stroke complicated with dyslipidemia require strict control of LDL‑C levels to reduce the risks of disease recurrence and cardiovascular events. However, a considerable number of patients still face difficulties in lipid management in clinical practice. Approximately 20%–30% of patients fail to achieve the LDL‑C target of below 1.8 mmol/L even after treatment with moderate-to-high intensity statins combined with ezetimibe. In addition, 5%–10% of patients cannot receive conventional statin therapy due to severe statin intolerance, resulting in poor lipid control and persistently elevated recurrence risk.

The advent of PCSK9 inhibitors has broken through the limitations of traditional lipid-lowering drugs. Featuring powerful lipid-lowering potency, favorable safety profile, and independence from hepatic metabolic enzyme systems, they provide an effective approach to addressing the above clinical dilemmas.

In recent years, multiple large-scale clinical studies have confirmed the remarkable efficacy of PCSK9 inhibitors in lowering LDL-C and reducing the risk of cardiovascular events, with clear benefits demonstrated particularly in the secondary prevention of ischemic stroke. Based on the latest clinical guidelines and research evidence, this article systematically reviews the mechanism of action, clinical application, safety profile, and research progress of PCSK9 inhibitors. It aims to provide new insights into individualized lipid-lowering therapy for patients with ischemic stroke complicated by dyslipidemia, and promote the development of clinical lipid-lowering treatment toward precision and high efficacy.

2、Mechanism of Action and Classification of PCSK9 Inhibitors

2.1 Core Mechanism of Action

PCSK9 is a serine protease synthesized and secreted by the liver. Its physiological function is to bind to LDL receptors on the surface of hepatocytes, mediate the endocytosis and degradation of LDL receptors, thereby reducing the hepatic uptake of circulating LDL-C and maintaining cholesterol homeostasis in the body.

In patients with dyslipidemia, elevated PCSK9 levels can markedly reduce the number of LDL receptors and impair the liver’s capacity to clear LDL-C. This consequently raises serum LDL-C levels and accelerates the progression of atherosclerosis.

PCSK9 inhibitors specifically bind to circulating PCSK9 and block its interaction with LDL receptors, thereby inhibiting the degradation of LDL receptors. This increases the quantity and activity of LDL receptors on the surface of hepatocytes, markedly improves the liver’s efficiency in uptake and metabolism of circulating LDL‑C, and achieves potent lipid‑lowering effects.

Compared with statins and ezetimibe, PCSK9 inhibitors exert a more direct mechanism of action. Instead of affecting cholesterol synthesis and absorption, they function by regulating the metabolic pathway of LDL receptors. The three types of agents have complementary action targets, providing a mechanistic basis for combined lipid‑lowering therapy.

In addition, several studies have indicated that PCSK9 inhibitors may further reduce the risk of cardiovascular events through lipid‑independent effects, such as suppressing inflammatory responses, improving vascular endothelial function, and stabilizing atherosclerotic plaques. Their pleiotropic effects remain under in‑depth investigation.

2.2 Classification and Administration of Drugs

Currently, clinically available PCSK9 inhibitors are mainly divided into two categories: monoclonal antibodies and small interfering RNA (siRNA) agents. Both are formulated for injection, featuring convenient administration and satisfactory patient compliance.

Monoclonal antibodies are the most widely used type in clinical practice, with representative drugs including evolocumab and alirocumab. They bind specifically to the active site of human PCSK9, block its combination with LDL receptors, and exert a rapid and remarkable lipid-lowering effect.

The recommended regimen of evolocumab is 140 mg subcutaneously every two weeks, or 420 mg subcutaneously once monthly. For alirocumab, the standard dose is 75 mg or 150 mg via subcutaneous injection every two weeks, with dosage adjustable according to the patient’s lipid levels.

The small interfering RNA (siRNA) class of PCSK9 inhibitors is represented by inclisiran. By adopting RNA interference technology, it suppresses the expression of the hepatic PCSK9 gene and reduces PCSK9 synthesis at the source, exhibiting long-acting lipid-lowering characteristics.

The recommended administration regimen of inclisiran is a subcutaneous injection of 284 mg for the first dose, followed by a second dose after 3 months, and subsequent maintenance doses once every 6 months. This regimen greatly reduces the frequency of administration, making it particularly suitable for patients requiring long-term treatment who are unable to receive frequent injections.

The two categories of PCSK9 inhibitors deliver comparable lipid-lowering potency, while the siRNA agents boast superior long-acting properties, offering more individualized therapeutic options for clinical practice.

3、Clinical Efficacy of PCSK9 Inhibitors

3.1 Lipid-lowering Efficacy

PCSK9 inhibitors exhibit significantly stronger lipid-lowering potency than traditional lipid-lowering drugs and can achieve a substantial reduction in LDL-C levels. Clinical studies have shown that monotherapy with monoclonal antibody-based PCSK9 inhibitors (evolocumab and alirocumab) can reduce serum LDL-C levels by 50%–60%. When combined with statins, they can further lower LDL-C by an additional 40%–50% on the basis of statin treatment. Even in patients who fail to reach lipid targets after moderate-to-high intensity statin combined with ezetimibe therapy, the addition of PCSK9 inhibitors can raise the LDL-C attainment rate (<1.8 mmol/L) to more than 90%.

The lipid-lowering efficacy of small interfering RNA PCSK9 inhibitors (inclisiran) is equally remarkable. The initial injection reduces LDL-C by 40%–50%, and the second dose administered three months later sustains the lipid-lowering effect. Long-term treatment enables stable control of LDL-C levels within the target range.

In addition, PCSK9 inhibitors can moderately improve other lipid profiles: they slightly decrease total cholesterol and triglyceride levels while mildly elevating high-density lipoprotein cholesterol levels, further optimizing lipid metabolism.

Notably, the lipid-lowering effect of PCSK9 inhibitors is not affected by age, gender, or mild to moderate hepatic and renal dysfunction, maintaining stable therapeutic efficacy even in special patient populations.

3.2 Efficacy in the Prevention of Cardiovascular Events

PCSK9 inhibitors not only exert potent lipid‑lowering effects but also significantly reduce the risk of cardiovascular events in patients with ischemic stroke complicated by dyslipidemia, with well‑established benefits particularly in secondary prevention.

The FOURIER trial demonstrated that evolocumab combined with statin therapy reduced the risk of recurrent stroke by 15% and the risk of major adverse cardiovascular events (including stroke, myocardial infarction, and cardiovascular death) by 20% in extremely high‑risk patients with recent ischemic stroke or transient ischemic attack (TIA). Such benefits began to emerge as early as 6 months after treatment initiation and continued to accumulate during long‑term therapy (median follow‑up of 2.2 years).

The ODYSSEY OUTCOMES trial confirmed that alirocumab added to statin therapy lowered the all‑cause mortality risk by 15% and cardiovascular mortality risk by 20% in patients with ischemic stroke. Greater clinical benefits were observed with lower achieved LDL‑C levels, and no relevant safety concerns emerged even when LDL‑C was reduced below 1.0 mmol/L.

Clinical studies of small interfering RNA agents have likewise shown that inclisiran can markedly decrease cardiovascular event risk in extremely high‑risk populations, with long‑term benefits comparable to those of monoclonal antibody PCSK9 inhibitors.

Furthermore, for statin‑intolerant patients who cannot receive statin therapy, PCSK9 inhibitor monotherapy also significantly reduces the risks of stroke recurrence and cardiovascular events, providing an effective strategy for cardiovascular risk management in this patient subgroup.

4、Clinical Application Strategies of PCSK9 Inhibitors

4.1 Applicable Population

The clinical application of PCSK9 inhibitors is prioritized for extremely high-risk patients with ischemic stroke (IS) complicated by dyslipidemia, specifically including the following populations: patients whose LDL-C still fails to reach the target (<1.8 mmol/L) after treatment with moderate-to-high intensity statins combined with ezetimibe; patients with severe statin intolerance (such as severe muscle injury and abnormal liver function) who are unable to receive statin therapy and present with significantly elevated blood lipid levels; and IS patients complicated with familial hypercholesterolemia. Such patients have markedly elevated LDL-C levels and limited response to traditional lipid-lowering drugs, whereas PCSK9 inhibitors can effectively control blood lipids and reduce the risk of recurrence.

In addition, for extremely high-risk IS patients complicated with diabetes, coronary heart disease, or stage 3–4 chronic kidney disease with poor lipid control, early initiation of PCSK9 inhibitors may be considered to rapidly achieve lipid targets and lower the risk of cardiovascular events. For elderly extremely high-risk patients aged 75 years and above, PCSK9 inhibitors demonstrate a favorable safety profile. They can be administered after evaluating that the benefits outweigh the risks without dose adjustment, providing a safe and potent lipid-lowering option for the elderly population.

4.2 Medication Regimen and Dose Adjustment

The medication regimen of PCSK9 inhibitors should be individualized according to patient classification, blood lipid levels, and drug categories.For patients who fail to achieve lipid targets after statin combined with ezetimibe therapy, PCSK9 inhibitors can be directly added. Monoclonal antibodies are administered at standard doses: evolocumab 140 mg every two weeks or 420 mg monthly, and alirocumab 75 mg or 150 mg every two weeks. The small interfering RNA agent inclisiran is given at a fixed dose of 284 mg once every six months. Blood lipids should be re-examined 4–8 weeks after medication initiation, and doses may be adjusted based on target attainment (e.g., alirocumab can be increased from 75 mg to 150 mg).

For statin-intolerant patients, PCSK9 inhibitor monotherapy can be adopted at the same dosage as in combined therapy. If the LDL-C reduction is insufficient, combination with ezetimibe 10 mg daily may be added to further enhance the lipid-lowering effect.For patients with familial hypercholesterolemia, a triple therapy regimen consisting of a PCSK9 inhibitor, a statin at the tolerated dose, and ezetimibe is recommended to maximally lower LDL-C levels and delay the progression of atherosclerosis.

During dose adjustment, it should be noted that the lipid-lowering effect of PCSK9 inhibitors is dose-dependent, and blind dose escalation is not recommended. If lipid targets remain unmet after standard-dose treatment, factors such as patient compliance and lifestyle should be evaluated, and additional lipid-lowering agents may be combined when necessary.

5、Safety and Adverse Reaction Management of PCSK9 Inhibitors

PCSK9 inhibitors demonstrate an overall favorable safety profile with a low incidence of adverse reactions, most of which are mild to moderate. They are better tolerated than high-intensity statins, and their long-term safety has been validated by numerous clinical studies. Adverse reactions are predominantly localized to injection sites, while systemic side effects are rare. Their specific characteristics and management strategies are outlined below.

Injection site reaction is the most common adverse event, with an incidence of 5%–10%. Manifestations include local redness, swelling, pain, pruritus and induration, which mostly occur at the initial stage of treatment, last for a short duration (1–3 days), and resolve spontaneously with repeated administration.

Management measures: Rotate injection sites (abdomen, lateral thigh) and avoid repeated injections at the same location; apply local compression for 5–10 seconds after injection without rubbing. For marked local reactions, cold compresses can relieve symptoms, and drug discontinuation is generally unnecessary.

The incidence of systemic adverse reactions is extremely low. Occasional events such as headache, dizziness, fatigue and nausea occur in less than 3% of patients, and are mostly transient without interfering with continued treatment. Rare hypersensitivity reactions (rash, urticaria, angioedema) have an incidence below 0.1%. Once these occur, the drug should be discontinued immediately with symptomatic treatment, and subsequent reuse of this class of agents should be avoided.

Notably, PCSK9 inhibitors have no adverse impact on liver function, muscle function or glucose metabolism. For patients complicated with diabetes or mild to moderate hepatic and renal insufficiency, no additional adjustment of monitoring frequency is required, reflecting a prominent safety advantage.

At present, there is no clear evidence of long-term safety risks associated with PCSK9 inhibitors. Long-term follow-up studies (over 5 years) have shown no unfavorable effects on all-cause mortality or malignancy incidence, supporting their safe application in long-term lipid-lowering therapy.

Nevertheless, safety data remain limited in patients with severe hepatic insufficiency, severe infection, as well as pregnant and lactating women, for whom PCSK9 inhibitors should be used with caution or avoided altogether.

6、Latest Research Progress and Future Prospects

In recent years, research on PCSK9 inhibitors has continued to advance steadily, yielding remarkable progress in expanding mechanisms of action, broadening clinical indications, and developing novel pharmaceutical agents.

In terms of mechanism of action, accumulating evidence indicates that beyond regulating lipid metabolism, PCSK9 inhibitors exert lipid-independent cardiovascular protection. They can suppress the release of inflammatory cytokines, alleviate vascular endothelial injury, and inhibit platelet aggregation, thereby further reducing the risk of cardiovascular events. Their beneficial effect on stabilizing atherosclerotic plaques is independent of lipid-lowering efficacy, providing additional theoretical evidence for their clinical benefits.

With regard to clinical application, multiple studies have explored the value of PCSK9 inhibitors in the primary prevention of ischemic stroke. Preliminary findings demonstrate that in high-risk individuals with markedly elevated LDL-C but no prior stroke history and multiple cardiovascular risk factors, PCSK9 inhibitors can significantly reduce the risk of first-ever ischemic stroke, offering a new strategy for primary prevention. Meanwhile, studies on combined therapy with other novel lipid-lowering agents are ongoing. Combination with ATP citrate lyase inhibitors is expected to achieve more potent lipid-lowering effects, providing an optimized therapeutic solution for patients with severe dyslipidemia.

In novel drug development, oral PCSK9 inhibitors have entered clinical trials. The oral formulation can substantially improve patient adherence and is expected to become a mainstream alternative to injectable preparations in the future. Furthermore, research on PCSK9-targeted gene editing therapy is progressing rapidly. The CRISPR-Cas9 technique can edit the PCSK9 gene to achieve long-term or even permanent reduction of LDL-C, bringing potential curative prospects for refractory dyslipidemia such as familial hypercholesterolemia.

Nevertheless, PCSK9 inhibitors still have certain limitations. Their relatively high cost restricts long-term accessibility for some patients. In addition, evidence regarding safety and efficacy remains insufficient in special populations, including patients with severe hepatic or renal insufficiency and children, requiring further clinical investigation.

In the future, with advances in pharmaceutical research, reduced drug costs, and the accumulation of more real-world clinical data, PCSK9 inhibitors are expected to play an increasingly vital role in the prevention and management of ischemic stroke combined with dyslipidemia, ushering in a new era of precise, potent, and long-acting lipid-lowering therapy.

7、Conclusion

As a novel class of potent lipid-lowering agents, PCSK9 inhibitors markedly reduce LDL-C levels through a unique mechanism of action, while significantly lowering the risks of stroke recurrence and major adverse cardiovascular events in extremely high-risk patients with ischemic stroke complicated by dyslipidemia. With a favorable safety profile, they provide an effective solution to the clinical limitations of conventional lipid-lowering therapies.

PCSK9 inhibitors have well-established clinical value in extremely high-risk patients failing to achieve lipid targets, statin-intolerant individuals, and patients with familial hypercholesterolemia. They also feature convenient administration and high patient adherence.

In clinical practice, it is essential to strictly define the applicable population for PCSK9 inhibitors, select appropriate drug types and administration regimens based on individual patient conditions, and combine pharmacological treatment with lifestyle intervention to achieve precise lipid control.

In the future, with the development of new formulations, further advancement of clinical research, and improved drug accessibility, PCSK9 inhibitors are expected to become a cornerstone therapy for lipid management in extremely high-risk patients with ischemic stroke and dyslipidemia, offering strong support for reducing disease burden and improving long-term patient prognosis.