"新時(shí)代降脂治療：全方位了解PCSK9抑制劑與Inclisiran"

("Lipid-Lowering Therapies in the New Era: A Comprehensive Understanding of PCSK9 Inhibitors and Inclisiran")

1. 心血管疾病與 LDL-C

Cardiovascular disease and LDL-C

以動(dòng)脈粥樣硬化性心血管疾?。╝therosclerotic cardiovascular disease, ASCVD）為主的心血管疾病（cardiovascular disease, CVD）是我國城鄉(xiāng)居民第一位死因，低密度脂蛋白膽固醇（low-density lipoprotein cholesterol, LDL-C）是 ASCVD 的致病性危險(xiǎn)因素。

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death among urban and rural residents in China, and elevated low-density lipoprotein cholesterol (LDL-C) is a risk factor for ASCVD[1, 2].

2. PCSK9 抑制劑嶄露頭角

PCSK9 Inhibitors Emerging

在降脂藥開發(fā)領(lǐng)域，PCSK9 是近年來一個(gè)新興的熱門靶點(diǎn)。在跨國制藥巨頭研發(fā)出靶向 PCSK9 的單抗藥物并在國內(nèi)獲批后，國內(nèi)相關(guān)藥物的研發(fā)也開始提速。已上市的 PCSK9 抑制劑主要有PCSK9單抗，而PCSK9小干擾RNA，即Inclisiran，在歐美及中國均已批準(zhǔn)上市。

In the field of lipid-lowering drug development, PCSK9 has emerged as a popular target in recent years. After multinational pharmaceutical giants developed monoclonal antibody drugs targeting PCSK9 and obtained approval in China, the development of related domestic drugs has also begun to accelerate. The main PCSK9 inhibitors that have been marketed are PCSK9 monoclonal antibodies. Inclisiran, a synthetic, double stranded, small interfering RNA (siRNA) has been approved for market inin Europe, US and China.

國內(nèi)已經(jīng)批準(zhǔn)了兩款進(jìn)口的 PCSK9 單抗，分別是依洛尤單抗（Evolocumab）以及阿利西尤單抗（Alirocumab）。目前這兩款藥物都已進(jìn)入醫(yī)保。

Two imported PCSK9 monoclonal antibodies have been approved in China, Evolocumab and Alirocumab. Both drugs are now covered by medical insurance.

商業(yè)保險(xiǎn)患者可以提前向保險(xiǎn)經(jīng)紀(jì)人詢問是否有降血脂針英克司蘭（Inclisiran）治療福利。如有福利，可在預(yù)約醫(yī)生門診評(píng)估是否適用針劑治療后，由工作人員幫助申請針劑治療福利擔(dān)保。

Patients with commercial insurance can inquire with their insurance broker in advance to see if there is coverage for lipid-lowering injection treatment with Inclisiran. If such benefits are available, after scheduling a consultation with a doctor to assess suitability for injection therapy, staff can assist with the application for injection treatment benefits guarantee.

圖1 Inclisiran （siRNA Blocker）是一種特異性抑制肝臟中 PCSK9 合成的新型藥物, siRNA進(jìn)行干預(yù)，可減少PCSK9的合成; 用PCSK9單克隆抗體干預(yù)，是阻斷PCSK9的作用[3]。

Figure 1 Inclisiran (siRNA Blocker) is a novel drug that specifically inhibits the synthesis of PCSK9 in the liver. siRNA intervention can reduce the synthesis of PCSK9; intervention with PCSK9 monoclonal antibodies is to block the action of PCSK9.

3. PCSK9抑制劑與心血管風(fēng)險(xiǎn)降低

PCSK9 inhibitors and cardiovascular risk reduction

降脂新藥如前蛋白轉(zhuǎn)化酶枯草溶菌素 9（preprotein converting enzyme subtilisin kexin 9，PCSK9）抑制劑的應(yīng)用，可使 LDL-C 水平降低 50%~70%，在他汀類藥物治療的基礎(chǔ)上進(jìn)一步減少主要不良心血管事件（major adverse cardiovascular event， MACE），再度證實(shí)了更大幅度降低 LDL-C 可帶來更多的心血管保護(hù)作用[4, 5]。

Research also demonstrated that the combination of lipid-lowering drugs and use of new drug classes such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors can reduce LDL-C levels by 50% to 70%, resulting in further reduction in major adverse cardiovascular events (MACE) based on statin therapy. This observation reaffirmed that additional substantial LDL-C reductions can lead to greater cardiovascular protection.

4. 特定治療組合

Specific treatment combinations

他汀類藥物治療后 LDL-C 未達(dá)標(biāo)時(shí)應(yīng)考慮聯(lián)合膽固醇吸收抑制劑和（或）PCSK9抑制劑。有研究顯示，提早使用 PCSK9 單抗可更早和更顯著降低 ASCVD 風(fēng)險(xiǎn)，且長時(shí)間使用 （≥ 7 年 ）具有良好的安全性[6]。PCSK9 抑制劑通過減少LDLR降解、增加LDLR數(shù)量而增加血漿LDL清除，在降脂機(jī)制上與他汀類藥物、膽固醇吸收抑制劑互補(bǔ)協(xié)同。

Combination of cholesterol absorption inhibitors and/or PCSK9 inhibitors should be considered when LDL-C targets are not met after statin therapy. Early use of PCSK9 monoclonal antibodies has been shown to reduce ASCVD risk earlier and more significantly, with good safety for prolonged use (≥7 years).PCSK9 inhibitors increase plasma LDL clearance by reducing LDLR degradation and increasing LDLR quantity, complementing and synergizing with statins and cholesterol uptake inhibitors in terms of lipid-lowering mechanisms.

5. PCSK9抑制劑作用機(jī)制

Mechanism of action of PCSK9 inhibitors

PCSK9 是肝臟合成的分泌型絲氨酸蛋白酶，可與LDLR 結(jié)合并使其降解，從而減少LDLR對血清 LDL-C的清除。通過抑制PCSK9，可阻止LDLR 降解，促進(jìn)LDL-C的清除。PCSK9單抗的作用機(jī)制系靶向作用于PCSK9蛋白[7]，

PCSK9 is a secreted serine protease synthesized by the liver that binds to and degrades LDLR, thereby reducing the clearance of serum LDL-C by LDLR. By inhibiting PCSK9, LDLR degradation can be prevented, and LDL-C clearance can be promoted. The mechanism of action of PCSK9 monoclonal antibodies is based on targeting the PCSK9 protein.

PCSK9抗體結(jié)合血漿 PCSK9，減少細(xì)胞表面的LDLR分解代謝，從而降低循環(huán)LDL-C水平[8]。目前獲批上市的有2種全人源單抗，分別是依洛尤單抗（evolocumab）和阿利西尤單抗（alirocumab）。研究證實(shí)依洛尤單抗和阿利西尤單抗可顯著降低平均LDL-C水平達(dá) 50%~70%。

PCSK9 antibodies bind to plasma PCSK9 and reduce the catabolism of LDLR on the cell surface, thereby reducing circulating LDL-C levels.

There are currently two human monoclonal antibodies approved for marketing, evolocumab and alirocumab. Studies have confirmed that evolocumab and alirocumab significantly reduce mean LDL-C levels by 50% to 70%.

圖2 PCSK9 是肝臟合成的分泌型絲氨酸蛋白酶，可與低密度脂蛋白( LDL) 受體結(jié)合并使其降解，從而減少 LDL 受體對血清 LDL-C 的清除。通過抑 制PCSK9，可阻止 LDL 受體降解，促進(jìn)LDL-C 清除。PCSK9單抗的作用機(jī)制系靶向作用于PCSK9蛋白[9].

Figure 2 PCSK9 is a secreted serine protease synthesized by the liver that binds to and degrades LDLR, thereby reducing the clearance of serum LDL-C by LDLR. By inhibiting PCSK9, LDLR degradation can be prevented, and LDL-C clearance can be promoted. The mechanism of action of PCSK9 monoclonal antibodies is based on targeting the PCSK9 protein.

6. 安全性與耐受性

Safety and Tolerance

依洛尤單抗140 mg 或阿利西尤單抗75 mg， 每兩周1次皮下注射，安全性和耐受性好，最常見的副作用包括注射部位發(fā)癢和流感樣癥狀[10]。

volocumab 140 mg or alirocumab 75 mg administered subcutaneously once every two weeks was safe and well tolerated, with the most common side effects including injection site itching and flu-like symptoms.

應(yīng)用 PCSK9 單抗后常?？蓪⒒颊叩?LDL-C 降至較低水平，有關(guān)PCSK9單抗的應(yīng)用時(shí)長是臨床關(guān)注的問題。最新的FOURIER開放標(biāo)簽擴(kuò)展研究 （FOURIER-Open Label Extension，F(xiàn)OURIER-OLE）提 示 ASCVD 患者應(yīng)用依洛尤單抗最長達(dá) 8.4 年（中位 5 年 ），中位 LDL-C 達(dá) 0.78 mmol/L 水平，其嚴(yán)重不良 事件、肌肉相關(guān)事件、新發(fā)糖尿病、出血性腦卒中和 神經(jīng)認(rèn)知事件等不良反應(yīng)發(fā)生率與安慰劑組相似[6]。

The latest FOURIER-open label Extension (FOURIEROLE) study suggests that ASCVD patients on evolocumab for up to 8.4 years (median 5 years) with a median LDL-C level of 0.78 mmol/L had serious adverse events, muscle-related events, new-onset diabetes mellitus The incidence of adverse events such as hemorrhagic stroke and neurocognitive events was similar to that of the placebo group.

應(yīng)用PCSK9 單抗后常?？蓪⒒颊叩腖DL-C 降至較低水平，有關(guān)PCSK9單抗的應(yīng)用時(shí)長是臨床關(guān)注的問題。最新的 FOURIER 開放標(biāo)簽擴(kuò)展研究（FOURIER-Open Label Extension，F(xiàn)OURIER-OLE）提示ASCVD患者應(yīng)用依洛尤單抗最長達(dá)8.4年（中位 5 年 ），中位 LDL-C 達(dá) 0.78 mmol/L 水平，其嚴(yán)重不良事件、肌肉相關(guān)事件、新發(fā)糖尿病、出血性腦卒中和 神經(jīng)認(rèn)知事件等不良反應(yīng)發(fā)生率與安慰劑組相似[6]。

Although the application of PCSK9 monoclonal antibodies often reduces LDL-C to lower levels in patients, the duration of application regarding PCSK9 monoclonal antibodies is a clinical concern. The latest FOURIER-open label Extension (FOURIEROLE) study suggests that ASCVD patients on evolocumab for up to 8.4 years (median 5 years) with a median LDL-C level of 0.78 mmol/L had serious adverse events, muscle-related events, new-onset diabetes mellitus The incidence of adverse events such as hemorrhagic stroke and neurocognitive events was similar to that of the placebo group.

專業(yè)知識(shí)小貼士：（開放標(biāo)簽擴(kuò)展研究（Open Label Extension Study）通常是在一項(xiàng)臨床試驗(yàn)完成后，為了進(jìn)一步收集藥物安全性和有效性數(shù)據(jù)而進(jìn)行的跟蹤研究。在這種研究中，參與者都知道他們正在接受的治療，也就是說沒有使用安慰劑（即沒有“盲測”）。

在您提到的FOURIER-OLE（FOURIER開放標(biāo)簽擴(kuò)展）研究的情況中，它意味著心血管事件的患者在最初FOURIER研究結(jié)束后，繼續(xù)使用依洛尤單抗，并且為期最長可達(dá)8.4年（平均大約5年）。研究目的可能是觀察這種藥物在長期使用后的效果和患者的安全性。簡單地說，研究者想要了解，當(dāng)患者長時(shí)間使用這種藥物時(shí)，它是否仍然能夠安全且有效地幫助他們降低再次出現(xiàn)心血管問題的風(fēng)險(xiǎn)）。

Expertise Tip:（An open-label extension study is typically a follow-up study conducted after the completion of a clinical trial to collect additional information on the safety and efficacy of a drug. In such a study, participants are aware of the treatment they are receiving, meaning there is no use of placebos (i.e., no "blinding").

In the case of the FOURIER-OLE (FOURIER Open Label Extension) study mentioned, it means that patients with cardiovascular events continued to receive the drug evolocumab following the conclusion of the initial FOURIER trial, for a period of up to 8.4 years (with a median duration of about 5 years). The purpose of the study is likely to observe the effects and safety of the drug over an extended period of usage. Simply put, the researchers want to understand whether this drug can continue to safely and effectively help patients lower their risk of experiencing cardiovascular issues again when used over a long term).

7. 適應(yīng)人群與臨床應(yīng)用

Target Population and Clinical Application

PCSK9抑制劑的應(yīng)用范圍正在不斷拓展，涵蓋不同的年齡群體和具有更高心血管風(fēng)險(xiǎn)的個(gè)體，包括老年人和有特定血脂代謝異常的患者，例如家族性高膽固醇血癥 (FH) 患者。

The scope of PCSK9 inhibitors is continually broadening, covering a variety of age groups and individuals with higher cardiovascular risks, including the elderly and patients with specific lipid metabolism disorders such as familial hypercholesterolemia (FH).

7.1特定人群的血脂管理

Lipid management for specific populations

要點(diǎn)提示：

特定人群是指具有某些共存疾?。ㄈ绺哐獕骸?糖尿病、CKD、腦卒中）、特殊生理狀態(tài)（妊娠）、 兒童、高齡老年人及特殊血脂代謝異常（家族性高 膽固醇血癥）的患者。其血脂代謝狀態(tài)及對藥物治療的反應(yīng)具有一定的特殊性，所以需要采取更為個(gè)體化的血脂管理策略。

Key points: Specific populations are patients with certain coexisting diseases (e.g., hypertension, diabetes, CKD, stroke), special physiological states (pregnancy), children, elderly people of advanced age, and special lipid metabolism abnormalities (familial hypercholesterolemia). Their lipid metabolism status and response to drug therapy are somewhat specific, so a more individualized lipid management strategy is needed.

他汀類藥物聯(lián)合膽固醇吸收抑制劑或（和 ）PCSK9單抗的研究顯示，合并糖尿病的 ASCVD患者可從強(qiáng)化降脂中獲益更多。兩項(xiàng)PCSK9抑制劑的二級(jí)預(yù)防研究中，入選患者的年齡范圍分別為 40~80 歲[4] 和≥ 18 歲[11] ，均包含了≥ 75 歲的人群， 且在 FOURIER 研究中的分層分析顯示，≥ 69 歲的 人群從 PCSK9 單抗降脂治療中的獲益與＜ 69 歲的 人群一致 [12]。綜合以上證據(jù)提示≥ 75 歲的 ASCVD 患者可與＜75歲患者采取同樣的降脂原則。

The age range of patients enrolled in the two secondary prevention studies of PCSK9 inhibitors was 40 to 80 years[10] and ≥ 18 years,[77] respectively, both of which included those ≥ 75 years, and a stratified analysis in the FOURIER study showed that those ≥ 69 years benefited from lipid-lowering therapy with PCSK9 monoclonal antibodies in consistent with those < 69 years.[206] Overall, this evidence suggests that ASCVD patients ≥ 75 years of age can be treated with the same lipid-lowering principles as patients < 75 years of age

專業(yè)知識(shí)小貼士：（二級(jí)預(yù)防研究是一類醫(yī)學(xué)研究，著重于防止已經(jīng)出現(xiàn)某種疾病的病人進(jìn)一步惡化或再次發(fā)生相關(guān)健康問題。在心血管領(lǐng)域，二級(jí)預(yù)防通常指的是對那些已經(jīng)有過心臟病發(fā)作、中風(fēng)或其他心血管事件的病人實(shí)施的干預(yù)措施。

具體到PCSK9抑制劑的二級(jí)預(yù)防研究，這意味著這項(xiàng)研究可能集中在已經(jīng)有過心血管事件的病人上，通過給予他們PCSK9抑制劑來降低他們未來出現(xiàn)心血管事件的風(fēng)險(xiǎn)。PCSK9抑制劑是一種降低血液中低密度脂蛋白膽固醇（LDL-C，又稱為“壞”膽固醇）的藥物，它有助于降低心臟病和其他心血管疾病的風(fēng)險(xiǎn)）。

Expertise Tip:（Secondary prevention studies are a category of medical research focused on preventing further deterioration or recurrence of health issues in patients who have already experienced a specific disease. In the cardiovascular field, secondary prevention typically refers to interventions for patients who have already suffered a heart attack, stroke, or other cardiovascular events.

Specifically, secondary prevention studies involving PCSK9 inhibitors would imply that the research is concentrated on patients who have experienced cardiovascular events, with the aim of reducing their risk of future cardiovascular incidents by administering PCSK9 inhibitors. PCSK9 inhibitors are a type of medication that lowers the levels of low-density lipoprotein cholesterol (LDL-C, also known as "bad" cholesterol) in the blood, which helps decrease the risk of heart disease and other cardiovascular conditions）.

8. Inclisiran：新興的PCSK9小干擾RNA

Inclisiran: An Emerging PCSK9 Small Interfering RNA

Inclisiran是PCSK9小干擾RNA，研究表明，其LDL-C降幅與PCSK9單抗相當(dāng)而作用更持久，注射一劑療效可維持半年[13]。屬超長效PCSK9抑制劑。增加患者治療的依從性為其主要優(yōu)勢。

Inclisiran is a PCSK9 small interfering RNA, and studies have shown that its LDL-C reduction rate is comparable to that of PCSK9 monoclonal antibodies while its effects are longer lasting, and the efficacy of one injection can be maintained for six months. Which is an ultra-long-acting PCSK9 inhibitor. Increasing patient compliance with treatment is its main advantage.

8.1 全球首款PCSK9 siRNA藥物--英克西蘭（Inclisiran）

適應(yīng)癥： 本品可作為飲食的輔助療法，用于成人原發(fā)性高膽固醇血癥（雜合子型家族性和非家族性）或混合型血脂異?；颊叩闹委煟?nbsp;

? 在接受最大耐受劑量的他汀類藥物治療仍無法達(dá)到 LDL-C 目標(biāo)的患者中，與他汀類藥物、或者與他汀類藥物及其他降脂療法聯(lián)合用藥，或者 

? 在他汀類藥物不耐受或禁忌使用的患者中，單獨(dú)用藥或與其他降脂療法聯(lián)合用藥[14]。

Inclisiran, the world's first PCSK9 siRNA drug

Indications: Inclisiran is indicated as an adjunct to diet and statin therapy for the treatment of adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce low-density lipoprotein cholesterol (LDL-C).

In patients who are unable to achieve LDL-C goals with the maximum      tolerated dose of statin therapy, either in combination with statins, or      with statins and other lipid-lowering therapies, or

In patients who are statin-intolerant or for whom statins are      contraindicated, as monotherapy or in combination with other      lipid-lowering therapies.

推薦用法用量：推薦給藥劑量為單次皮下注射 284 mg 本品：首次給藥后，在 3 個(gè)月時(shí)再次給藥， 然后每 6 個(gè)月給藥一次。 

The recommended dosage of Inclisiran, is 284 mg administered as a single subcutaneous injection initially, again at 3 months, and then every 6 months.

9. 高級(jí)化學(xué)修飾與GalNAc遞送系統(tǒng)

The Application of Advanced Chemical Modifications and the GalNAc Delivery System

9.1 長程藥效：得益于siRNA藥物化學(xué)修飾技術(shù)的不斷進(jìn)步

英克西蘭siRNA的“高級(jí)ESC（Enhanced Stability Chemistry）化學(xué)修飾”，能增強(qiáng)siRNA對核酸酶的抵抗能力，延長其在肝細(xì)胞內(nèi)的存活時(shí)間[15, 16]

Prolonged Drug Efficacy: Thanks to the continuous advancement in siRNA medicinal chemical modification technology,

Inclisiran's "advanced ESC (Enhanced Stability Chemistry) chemical modification" can enhance the resistance of siRNA to nucleases, thus extending its survival time within hepatocytes.

9.2 靶向肝臟：GalNAc遞送系統(tǒng)

N-乙酰半乳糖胺（GalNAc）與RNA藥物偶聯(lián)，遞送至肝臟[17]

Liver Targeting: GalNAc Delivery System

N-acetylgalactosamine (GalNAc) conjugated with RNA therapeutics is delivered to the liver.

9.3 高度特異：siRNA需要整條RNA鏈完全匹配才能激活RISC[18]

siRNA（小干擾RNA）是一種用來干預(yù)生物體內(nèi)基因表達(dá)的工具。它的工作機(jī)制是通過精確地與目標(biāo)基因的RNA序列配對，進(jìn)而引導(dǎo)一種叫RISC（RNA誘導(dǎo)沉默復(fù)合體）的蛋白質(zhì)復(fù)合體來降解這些RNA序列，阻止其轉(zhuǎn)化成蛋白質(zhì)。這種配對需要非常精確，siRNA的整條RNA鏈需要與目標(biāo)基因的RNA序列完全匹配，只有這樣，RISC復(fù)合體才會(huì)被正確地激活，并且特定的基因表達(dá)才會(huì)被抑制。

簡單來說，siRNA就像是一個(gè)定制的“指令碼”，只有當(dāng)它完全符合特定的“目標(biāo)代碼”時(shí)，才能發(fā)動(dòng)攻擊，關(guān)閉那個(gè)基因的活動(dòng)。這種高度的特異性意味著siRNA可以非常精確地對特定基因進(jìn)行干預(yù)，同時(shí)降低了對其他非目標(biāo)基因錯(cuò)傷的可能性。

High Specificity: siRNA requires complete matching of the entire RNA strand to activate RISC.

siRNA (small interfering RNA) is a tool used to intervene in gene expression within an organism. Its mechanism of action involves precise pairing with the RNA sequence of the target gene, which then directs a protein complex known as RISC (RNA-induced silencing complex) to degrade these RNA sequences and prevent them from being translated into proteins. This pairing must be highly precise; the entire RNA chain of the siRNA must perfectly match the RNA sequence of the target gene. Only with such a complete match can the RISC complex be properly activated, and the expression of the specific gene can be inhibited.

In simpler terms, siRNA acts like a custom "instruction code" that can initiate an attack and shut down gene activity only when it completely corresponds to the specific "target code." This high specificity means that siRNA can intervene in a very precise manner on particular genes while reducing the likelihood of off-target effects on other genes.

9.4 高安全性：化學(xué)修飾、GalNAc遞送系統(tǒng)降低siRNA潛在風(fēng)險(xiǎn)

High Safety: Chemical modifications and the GalNAc delivery system reduce the potential risks of siRNA.

10 藥品使用：

本藥品是處方藥，需要醫(yī)生開具處方，并根據(jù)患者情況合理使用。

ADMINISTRATION

This drug is a prescription drug that requires a doctor's prescription and is used appropriately according to the patient's condition.

參考文獻(xiàn)

References

1           中國血脂管理指南（2023 年）.

2           2023 China Guidelines for Lipid Management.

3           Rosenson RS, Hegele RA, Fazio S, Cannon CP. The Evolving Future of PCSK9 Inhibitors. J Am Coll Cardiol 2018; 72: 314-29.

4           Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017; 376: 1713-22.

5           Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med 2019; 380: 11-22.

6           O'Donoghue ML, Giugliano RP, Wiviott SD, Atar D, Keech A, Kuder JF, et al. Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease. Circulation 2022; 146: 1109-19.

7           Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003; 34: 154-6.

8           Norata GD, Tibolla G, Catapano AL. Targeting PCSK9 for hypercholesterolemia. Annu Rev Pharmacol Toxicol 2014; 54: 273-93.

9           Ferro CJ, Mark PB, Kanbay M, Sarafidis P, Heine GH, Rossignol P, et al. Lipid management in patients with chronic kidney disease. Nat Rev Nephrol 2018; 14: 727-49.

10         Cicero AF, Tartagni E, Ertek S. Safety and tolerability of injectable lipid-lowering drugs: a review of available clinical data. Expert Opin Drug Saf 2014; 13: 1023-30.

11         Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med 2018; 379: 2097-107.

12         Sever P, Gouni-Berthold I, Keech A, Giugliano R, Pedersen TR, Im K, et al. LDL-cholesterol lowering with evolocumab, and outcomes according to age and sex in patients in the FOURIER Trial. Eur J Prev Cardiol 2021; 28: 805-12.

13         Fitzgerald K, White S, Borodovsky A, Bettencourt BR, Strahs A, Clausen V, et al. A Highly Durable RNAi Therapeutic Inhibitor of PCSK9. N Engl J Med 2017; 376: 41-51.

14         英克司蘭鈉注射液(樂可為) 藥品說明書 核準(zhǔn)日期：2023年08月22日.

15         Hu B, Zhong L, Weng Y, Peng L, Huang Y, Zhao Y, et al. Therapeutic siRNA: state of the art. Signal Transduct Target Ther 2020; 5: 101.

16         Maraganore J. Reflections on Alnylam. Nat Biotechnol 2022; 40: 641-50.

17         Erik Bush AN, Tao Pei, Ine Kuipers, Weijun Cheng, Holly Hamilton, Julia Hegge, Xiaokai Li, Agnieszka Glebocka, Rui Zhu, Bo Chen, Philip Kuehl, Thomas Schluep, Zhen Li. Targeting aENaC with an epithelial RNAi trigger delivery platform for the treatment of cystic fibrosis. European Respiratory Journal 2018; 2018 52: OA514.

18         Dyrbus K, Gasior M, Penson P, Ray KK, Banach M. Inclisiran-New hope in the management of lipid disorders? J Clin Lipidol 2020; 14: 16-27.

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