检索问题
治疗动脉粥样硬化的药物或活性成分有哪些？其对应的制剂进入到临床试验阶段的有哪些？
动脉粥样硬化是一种慢性疾病，其特征是脂质堆积和中等至大型动脉的慢性炎症，是全球心血管疾病发病和死亡的主要原因 。尽管他汀类药物等传统疗法在降低低密度脂蛋白胆固醇（LDL-C）和心血管疾病（CVD）发病率及死亡率方面发挥了关键作用，但仍有许多患者面临残余风险，因此需要开发新的治疗策略 。
目前治疗动脉粥样硬化的药物或活性成分主要可以分为以下几类：
一、针对脂质代谢的疗法
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他汀类药物 (Statins) 他汀类药物被认为是治疗动脉粥样硬化的主要标准疗法，通过降低血浆低密度脂蛋白胆固醇（LDL-C）和适度增加高密度脂蛋白胆固醇（HDL-C）来发挥作用 。除了降脂作用，他汀类药物还具有非脂质相关的抗炎作用，已被证实可直接作用于多种细胞类型和途径，抑制炎症反应，从而对动脉粥样硬化产生血管保护作用 。他汀类药物的抗炎效果被认为是其在动脉粥样硬化中总体积极作用的重要组成部分 。
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PCSK9 抑制剂 (PCSK9 Inhibitors) PCSK9（前蛋白转化酶枯草杆菌蛋白酶/Kexin 9型）在低密度脂蛋白（LDL）代谢中扮演重要角色 。通过抑制PCSK9与低密度脂蛋白受体（LDLR）的结合，可以显著降低血浆LDL-C水平 。
- 单克隆抗体 (Monoclonal Antibodies)：依洛尤单抗 (Evolocumab) 和阿利洛尤单抗 (Alirocumab) 是已开发的PCSK9抑制性单克隆抗体，已被证明可使LDL-C水平降低高达60%，并能逆转和稳定冠状动脉粥样硬化，降低心血管风险 。
- RNA 干扰 (RNA interference, RNAi)：英利司兰 (Inclisiran) 是一种RNA干扰药物，作为PCSK9抑制剂，在临床试验中显示出显著降低LDL-C的效果 。一项网络荟萃分析显示，英利司兰在降低LDL-C方面优于他汀类药物和依折麦布，并且与阿利洛尤单抗和依洛尤单抗的LDL-C降低效果相当，同时具有较低的给药频率和可比的安全谱，对依从性差或对其他药物有副作用的患者尤其有前景 。
- 口服小分子抑制剂：虽然单克隆抗体和siRNA注射剂在降低LDL-C方面有效，但口服PCSK9抑制剂的开发一直面临挑战 。MK-0616 是一种新型口服宏环肽，通过 mRNA 显示筛选技术发现，并经结构导向药物设计优化，具有极高的PCSK9亲和力 (KD = 5pM) 和选择性 。在一项单剂量递增的I期临床试验中，MK-0616使游离、未结合血浆PCSK9几何平均值降低超过93%。在接受他汀治疗的患者中，20 mg MK-0616每日一次口服给药14天后，LDL-C几何平均值从基线降低了61% 。该研究验证了 mRNA 显示技术在发现新型口服治疗剂方面的应用，MK-0616 有望成为一种高效的降胆固醇疗法 。
- 疫苗和基因编辑：PCSK9 抑制的其他替代方法，如疫苗和基因编辑，也正在进行临床评估 。
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依折麦布 (Ezetimibe) 依折麦布是一种非他汀类降脂疗法，通常与他汀类药物联用，用于治疗高胆固醇血症患者，以降低心血管风险 。
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载脂蛋白(a) [Lp(a)] 靶向疗法 (Lipoprotein(a) [Lp(a)] Targeting Therapies) Lp(a) 由一个低密度脂蛋白样分子和载脂蛋白(a) [apo(a)] 颗粒组成，被认为是动脉粥样硬化性心血管疾病（ASCVD）的独立风险因素 。由于 Lp(a) 水平主要由遗传决定且在个体一生中几乎稳定，针对 Lp(a) 的药物开发一直较少 。
- 反义寡核苷酸 (Antisense Oligonucleotides, ASOs) 和 小干扰RNA (small interfering RNAs, siRNAs)：这些新型药物目前正在开发中，旨在靶向 Lp(a) 。
- Muvalaplin：一种口服 Lp(a) 形成抑制剂，其前景正在进一步分析中 。
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残余胆固醇靶向疗法 (Remnant Cholesterol Targeting Therapies) 残余胆固醇（甘油三酯富集脂蛋白中的胆固醇）血浆浓度升高与 ASCVD 风险增加相关 。观察性流行病学和孟德尔随机化研究强烈表明，升高的残余胆固醇是 ASCVD 的一个因果风险因素 。
- 载脂蛋白 CIII (apoCIII) 抑制剂：
- 血管生成素样蛋白 3 (ANGPTL3) 和 4 (ANGPTL4) 抑制剂：
- FGF21 类似物：这些新型药物已被开发，在甘油三酯水平高达10 mmol/L（880 mg/dL）的患者中，可将残余胆固醇水平降低50-80% 。大型心血管结局试验将提供这些药物临床益处的决定性证据。如果这些试验成功，残余胆固醇降低可能成为治疗他汀类药物治疗后非HDL胆固醇水平升高导致残余 ASCVD 风险患者的重要目标 。
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胆固醇酯转移蛋白 (CETP) 抑制剂 (Cholesteryl Ester Transfer Protein (CETP) Inhibitors) CETP 小分子抑制剂可以增加高密度脂蛋白胆固醇（HDL-C）水平 。然而，CETP 抑制剂似乎不能降低动脉粥样硬化疾病的风险 。
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载脂蛋白 A-I 模拟肽 (Apolipoprotein A-I Mimetic Peptides) HDL 疗法，包括重组 HDL、载脂蛋白 A-I Milano (ApoA-I Milano)、ApoA-I 模拟肽或全长 ApoA-I，在动物模型中显示出显著效果 。其中，一种名为 FAMP 的 ApoA-I 模拟肽通过 ABCA1 转运体有效清除胆固醇，并通过增强 HDL 的生物学功能，在不升高 HDL-C 水平的情况下作为抗动脉粥样硬化剂 。
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地拉普拉地 (Darapladib) 地拉普拉地是一种选择性脂蛋白相关磷脂酶 A2 (Lp-PLA2) 抑制剂 。Lp-PLA2 在动脉粥样硬化斑块破裂中扮演重要角色，而斑块破裂是导致缺血性死亡、心肌梗死、急性冠状动脉综合征和缺血性中风等临床事件的原因 。地拉普拉地代表了一类针对炎症以治疗高危动脉粥样硬化的新型治疗剂 。然而，针对 Lp-PLA2 的大型临床试验未能达到其主要终点 。
二、针对炎症通路的疗法
炎症在动脉粥样硬化的发生、发展和并发症中都扮演着关键角色 。因此，靶向炎症通路为预防和治疗动脉粥样硬化提供了有前景的新途径 。
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卡那奴单抗 (Canakinumab) 卡那奴单抗是一种中和白细胞介素-1β (IL-1β) 的抗体 。CANTOS（Canakinumab Anti-inflammatory Thrombosis Outcomes Study）研究表明，卡那奴单抗可以降低继发性预防中的复发性心血管事件，这表明从 NLRP3（NOD 样受体家族、pyrin 结构域包含蛋白 3）炎性体通过 IL-1β 到 IL-6 的通路是除了脂质疗法之外的一个有吸引力的研究和临床开发靶点 。卡那奴单抗的成功证实了炎症调控可以阻止动脉粥样硬化的临床并发症 。
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秋水仙碱 (Colchicine) 秋水仙碱是一种安全且廉价的抗炎药物，用于降低冠状动脉疾病继发预防中的心血管事件残余风险 。最近的荟萃分析显示，秋水仙碱相比安慰剂显著降低了主要不良心血管事件 (MACE)、心肌梗死、缺血性中风和复发性冠状动脉血运重建的发生率 。美国食品和药物管理局（FDA）最近已批准秋水仙碱用于此适应症 。
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p38 丝裂原活化蛋白激酶 (MAPK) 抑制剂 (p38 Mitogen-Activated Protein Kinase (MAPK) Inhibitors) p38 MAPK 通路被认为在动脉粥样硬化的炎症反应中发挥关键作用 。
- 洛司马替尼 (Losmapimod)：一种 p38 MAPK 抑制剂，但在临床试验中并未改变不良事件的发生率 。
- 丹霞调斑汤 (Danxia Tiaoban Decoction, DXTB)：一种传统中药方剂，通过多组学整合和实验验证，揭示其可能通过调节核心炎症和脂质相关通路，特别是 p38 MAPK 信号通路，以及 CSF1R、DPP4 和 MMP9 等核心基因来发挥治疗动脉粥样硬化的作用 。动物实验表明，DXTB 减少了脂质积累，抑制了 p38 MAPK 信号通路的激活，调节了核心基因的表达，并降低了 IL-1β、IL-6 和 TNFα 等炎症因子，从而减少了斑块面积 。
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白细胞黏附分子 P-选择素 抑制剂 (P-selectin Inhibitors) P-选择素抑制剂在试验中并未改变不良事件的发生率 。
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低剂量甲氨蝶呤 (Low-dose methotrexate) 尽管观察性研究前景广阔，但低剂量甲氨蝶呤在心血管炎症降低试验 (CIRT) 中并未降低炎症生物标志物或改变心血管结局 。
三、基因治疗和新型药物递送系统
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基因疗法 (Gene Therapies) 遗传药物，如小干扰 RNA (siRNA)、mRNA 或质粒 DNA，通过沉默致病基因、表达治疗性蛋白质或通过基因编辑应用，为治疗大多数疾病提供了潜在的基因疗法 。脂质纳米颗粒 (LNP) 系统是目前领先的非病毒递送系统，能够实现遗传药物的临床潜力 。LNP siRNA 系统已成功用于在全身给药后沉默肝细胞中的靶基因，并且已向 FDA 提交 LNP siRNA 药物申请以治疗甲状腺素转运蛋白诱导的淀粉样变性 。核酸类疗法，特别是 RNA 寡核苷酸和 siRNA，正在开发用于治疗动脉粥样硬化的相关风险因素 。针对 PCSK9、Lp(a)、ApoCIII 和 ANGPTL3 的 RNA 抑制剂已在 II-III 期临床试验中取得成功 。
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纳米载体递送系统 (Nano-scale Carriers for Drug Delivery) 纳米尺度载体被认为是解决当前药物洗脱球囊 (DEB) 涂层技术缺点的可能方法，有助于提高药物向动脉组织的转移效率，减少不必要的颗粒生成 。
进入临床试验阶段的药物或制剂
根据现有证据，以下药物或活性成分及其制剂已进入临床试验阶段：
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PCSK9 抑制剂：
- 单克隆抗体：依洛尤单抗 (Evolocumab) 和阿利洛尤单抗 (Alirocumab) 已在大型临床结局试验中证明其疗效，并已被批准用于临床 。
- RNA 干扰药物：英利司兰 (Inclisiran) 正在进行临床评估，并在一项网络荟萃分析中显示出与 PCSK9 单克隆抗体相当的 LDL-C 降低效果 。
- 口服宏环肽：MK-0616 已完成健康成人单剂量递增的 I 期临床试验，并在接受他汀治疗的患者中进行了多剂量试验，以评估其安全性、药代动力学和药效学 。
- 疫苗和基因编辑：这些替代方法目前正在进行临床评估 。
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Lp(a) 靶向疗法：
- 反义寡核苷酸 (ASOs) 和 小干扰RNA (siRNAs)：这些新型药物目前正在开发中并靶向 Lp(a) 。
- Muvalaplin：一种口服 Lp(a) 形成抑制剂，其前景正在进一步分析中 。
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残余胆固醇靶向疗法：
- 载脂蛋白 CIII (apoCIII) 抑制剂、血管生成素样蛋白 3 (ANGPTL3) 和 4 (ANGPLT4) 抑制剂、FGF21 类似物：这些药物正在进行大型心血管结局试验，以提供临床益处的决定性证据 。
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炎症通路靶向疗法：
- 卡那奴单抗 (Canakinumab)：作为 IL-1β 的抗体，已在 CANTOS 试验中显示出降低复发性心血管事件的益处 。
- 秋水仙碱 (Colchicine)：多项大型随机对照试验（如 COLCOT、LoDoCo2、CLEAR）已证明其在心血管事件继发预防中的疗效和安全性，并已被 FDA 批准用于此适应症 。
- 洛司马替尼 (Losmapimod)：p38 MAPK 抑制剂，已在试验中进行评估 。
- 丹霞调斑汤 (DXTB)：其作用机制通过多组学分析和动物实验进行了验证，显示出在减少脂质积累和炎症方面的潜力 。虽然初步研究已完成，但具体的临床试验阶段信息未明确指出，但其研究结果为未来临床应用提供了支持 。
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Bempedoic acid：一种非他汀类降脂疗法，已在临床试验中评估其降低 LDL-C 的效果 。
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核酸类疗法 (Nucleic Acid-Based Therapies)：
- ASOs 和 siRNAs：针对 PCSK9、Lp(a)、ApoCIII 和 ANGPTL3 的 RNA 抑制剂已在 II-III 期临床试验中取得成功 。
总结而言，治疗动脉粥样硬化的药物和活性成分种类繁多，包括传统的他汀类药物、新型的PCSK9抑制剂（单抗、siRNA、口服肽）、靶向Lp(a)和残余胆固醇的疗法，以及通过调节炎症通路（如IL-1β、NLRP3炎性体）发挥作用的抗炎药物。其中，PCSK9抑制剂（依洛尤单抗、阿利洛尤单抗、英利司兰）、口服PCSK9抑制剂MK-0616、Lp(a)靶向疗法（ASOs、siRNAs、muvalaplin）、残余胆固醇靶向药物（apoCIII、ANGPTL3/4抑制剂、FGF21类似物）、卡那奴单抗和秋水仙碱等均已进入或正在进行临床试验，并展现出不同程度的疗效和潜力 。这些新疗法的开发旨在解决现有治疗方案下的残余风险，为动脉粥样硬化患者提供更全面、有效的管理策略。
References
1Lipoprotein(a) and Atherosclerotic Cardiovascular Disease: Where Do We Stand?PubMed
Georgios Tsioulos, Dimitris Kounatidis, Natalia G Vallianou, et al.
Lipoprotein(a) [Lp(a)] consists of a low-density lipoprotein-like molecule and an apolipoprotein(a) [apo(a)] particle. Lp(a) has been suggested to be an independent risk factor of atherosclerotic cardiovascular disease (ASCVD). Lp(a) plasma levels are considered to be 70-90% genetically determined through the codominant expression of the gene. Therefore, Lp(a) levels are almost stable during an individual's lifetime. This lifelong stability, together with the difficulties in measuring Lp(a) levels in a standardized manner, may account for the scarcity of available drugs targeting Lp(a). In this review, we synopsize the latest data regarding the structure, metabolism, and factors affecting circulating levels of Lp(a), as well as the laboratory determination measurement of Lp(a), its role in the pathogenesis of ASCVD and thrombosis, and the potential use of various therapeutic agents targeting Lp(a). In particular, we discuss novel agents, such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) that are currently being developed and target Lp(a). The promising role of muvalaplin, an oral inhibitor of Lp(a) formation, is then further analyzed.
2Feasibility of remnant cholesterol as a therapeutic target for atherosclerotic cardio-vascular disease.PubMed
Anders Berg Wulff, Anette Varbo, Ask Tybjærg Nordestgaard, et al.
INTRODUCTION: Elevated plasma concentration of remnant cholesterol, the cholesterol in triglyceride-rich lipoproteins, is associated with increased risk of atherosclerotic cardiovascular disease (ASCVD) in large observational epidemiological and Mendelian randomization studies. Novel drugs with pronounced remnant cholesterol-lowering effects are developed; however, their effect on risk of ASCVD remains to be documented. AREAS COVERED: Observational epidemiological and Mendelian randomization studies and randomized controlled trials examine plasma remnant cholesterol levels as an emerging drug target for ASCVD prevention. EXPERT OPINION: Observational epidemiological and genetic studies strongly indicate that elevated remnant cholesterol is a causal risk factor for ASCVD. In randomized controlled trials of individuals with elevated plasma triglyceride levels up to 10 mmol/L (880 mg/dL), apoCIII and ANGPTL3 and 4 inhibitors and FGF21 analogues lower remnant cholesterol levels by 50-80%, and large cardiovascular outcome trials of these novel drugs are therefore well positioned to provide definitive evidence of clinical benefit. However, for these trials to succeed, lowering of remnant cholesterol must be accompanied by a lowering of total apolipoprotein B containing lipoproteins. If such trials succeed, remnant cholesterol lowering may become an important target for ASCVD prevention among patients with residual ASCVD risk due to elevated non-HDL cholesterol levels despite statin therapy.
3Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor.PubMed
Douglas G Johns, Louis-Charles Campeau, Puja Banka, et al.
BACKGROUND: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low density lipoprotein-cholesterol, but despite nearly 2 decades of effort, an oral inhibitor of PCSK9 is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable to small-molecule drug design. METHODS: Novel mRNA display screening technology was used to identify lead chemical matter, which was then optimized by applying structure-based drug design enabled by novel synthetic chemistry to identify macrocyclic peptide (MK-0616) with exquisite potency and selectivity for PCSK9. Following completion of nonclinical safety studies, MK-0616 was administered to healthy adult participants in a single rising-dose Phase 1 clinical trial designed to evaluate its safety, pharmacokinetics, and pharmacodynamics. In a multiple-dose trial in participants taking statins, MK-0616 was administered once daily for 14 days to characterize the safety, pharmacokinetics, and pharmacodynamics (change in low density lipoprotein cholesterol). RESULTS: MK-0616 displayed high affinity ( = 5pM) for PCSK9 in vitro and sufficient safety and oral bioavailability preclinically to enable advancement into the clinic. In Phase 1 clinical studies in healthy adults, single oral doses of MK-0616 were associated with >93% geometric mean reduction (95% CI, 84-103) of free, unbound plasma PCSK9; in participants on statin therapy, multiple-oral-dose regimens provided a maximum 61% geometric mean reduction (95% CI, 43-85) in low density lipoprotein cholesterol from baseline after 14 days of once-daily dosing of 20 mg MK-0616. CONCLUSIONS: This work validates the use of mRNA display technology for identification of novel oral therapeutic agents, exemplified by the identification of an oral PCSK9 inhibitor, which has the potential to be a highly effective cholesterol lowering therapy for patients in need.
4Targeting inflammation in atherosclerosis - from experimental insights to the clinic.PubMed
Oliver Soehnlein, Peter Libby
Atherosclerosis, a dominant and growing cause of death and disability worldwide, involves inflammation from its inception to the emergence of complications. Targeting inflammatory pathways could therefore provide a promising new avenue to prevent and treat atherosclerosis. Indeed, clinical studies have now demonstrated unequivocally that modulation of inflammation can forestall the clinical complications of atherosclerosis. This progress pinpoints the need for preclinical investigations to refine strategies for combatting inflammation in the human disease. In this Review, we consider a gamut of attractive possibilities for modifying inflammation in atherosclerosis, including targeting pivotal inflammatory pathways such as the inflammasomes, inhibiting cytokines, manipulating adaptive immunity and promoting pro-resolution mechanisms. Along with lifestyle measures, pharmacological interventions to mute inflammation could complement traditional targets, such as lipids and hypertension, to make new inroads into the management of atherosclerotic risk.
5Lipid Nanoparticle Systems for Enabling Gene Therapies.PubMed
Pieter R Cullis, Michael J Hope
Genetic drugs such as small interfering RNA (siRNA), mRNA, or plasmid DNA provide potential gene therapies to treat most diseases by silencing pathological genes, expressing therapeutic proteins, or through gene-editing applications. In order for genetic drugs to be used clinically, however, sophisticated delivery systems are required. Lipid nanoparticle (LNP) systems are currently the lead non-viral delivery systems for enabling the clinical potential of genetic drugs. Application will be made to the Food and Drug Administration (FDA) in 2017 for approval of an LNP siRNA drug to treat transthyretin-induced amyloidosis, presently an untreatable disease. Here, we first review research leading to the development of LNP siRNA systems capable of silencing target genes in hepatocytes following systemic administration. Subsequently, progress made to extend LNP technology to mRNA and plasmids for protein replacement, vaccine, and gene-editing applications is summarized. Finally, we address current limitations of LNP technology as applied to genetic drugs and ways in which such limitations may be overcome. It is concluded that LNP technology, by virtue of robust and efficient formulation processes, as well as advantages in potency, payload, and design flexibility, will be a dominant non-viral technology to enable the enormous potential of gene therapy.
6Statins and Inflammation.PubMed
Martin Satny, Jaroslav A Hubacek, Michal Vrablik
PURPOSE OF REVIEW: Chronic inflammation has been recognized as one of the most important pathophysiological mechanisms' initiation and progression of atherosclerosis. Statins belong to most successful therapeutic agents in the prevention and treatment of atherothrombotic vascular disease. Their non-lipid related effects including suppression of inflammation have been repeatedly proven in both experimental and clinical settings. RECENT FINDINGS: Recently, the importance of inflammation in the process of atherosclerosis has been confirmed by interventions targeting inflammation selectively. Clinical trial with selective inhibitor of a principal inflammatory mediator interleukin 1-beta - canakinumab - confirmed the notion of direct vasculoprotective effects of primarily targeting inflammation. This has increased interest in the non-lipid, pleiotropic and, particularly, anti-inflammatory effects of statins. Anti-inflammatory effects of statins have been proven both experimentally and in clinical settings beyond any doubt. They comprise a direct positive effect on not only many cell types and pathways that are lipid independent but, also, some that are mediated by lipid modification. Undoubtedly, suppression of inflammatory response by statins contributes to their generally positive action in atherosclerosis and represents an important part of the vasculo- and atheroprotective effect of this drug class.
7PCSK9 inhibitors and reduction in cardiovascular events: Current evidence and future perspectives.PubMed
Stephen J Nicholls
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in low-density lipoprotein (LDL) metabolism. Pharmacological PCSK9 inhibitors have been developed as a novel approach to treating dyslipidemia. This article reviews the spectrum of evidence implicating the role of PCSK9 in lipid metabolism and the clinical impact of PCSK9 inhibitors on lipid parameters and cardiovascular risk. Biochemical and genomic studies have established the role that PCSK9 plays in lipid metabolism and potential protection from cardiovascular disease observed in the setting of PCSK9 deficiency. This led to the development of inhibitory monoclonal antibodies (evolocumab, alirocumab) that produce dose-dependent lowering of LDL cholesterol up to 60%, with evidence of regression and stabilization of coronary atherosclerosis (GLAGOV, HUYGENS, PACMAN-AMI) and reduction in cardiovascular risk in large clinical outcomes trials (FOURIER, ODYSSEY Outcomes). More recent developments have witnessed alternative approaches to PCSK9 inhibition such as RNA interference (inclisiran), vaccines, and gene editing, which are currently undergoing clinical evaluation. PCSK9 inhibition has emerged as an important component of treatment approaches to lowering LDL cholesterol and plays an increasing role in preventive strategies.
8Novel Therapeutics and Upcoming Clinical Trials Targeting Inflammation in Cardiovascular Diseases.PubMed
Nicola Potere, Aldo Bonaventura, Antonio Abbate
Cardiovascular disease (CVD) remains a major health burden despite significant therapeutic advances accomplished over the last decades. It is widely and increasingly recognized that systemic inflammation not only represents a major cardiovascular risk and prognostic factor but also plays key pathogenic roles in CVD development and progression. Despite compelling preclinical evidence suggesting large potential of anti-inflammatory pharmacological interventions across numerous CVDs, clinical translation remains incomplete, mainly due to (1) yet undefined molecular signaling; (2) challenges of safety and efficacy profile of anti-inflammatory drugs; and (3) difficulties in identifying optimal patient candidates and responders to anti-inflammatory therapeutics, as well as optimal therapeutic windows. Randomized controlled trials demonstrated the safety/efficacy of canakinumab and colchicine in secondary cardiovascular prevention, providing confirmation for the involvement of a specific inflammatory pathway (NLRP3 [NACHT, LRR, and PYD domain-containing protein 3] inflammasome/IL [interleukin]-1β) in atherosclerotic CVD. Colchicine was recently approved by the US Food and Drug Administration for this indication. Diverse anti-inflammatory drugs targeting distinct inflammatory pathways are widely used for the management of other CVDs including myocarditis and pericarditis. Ongoing research efforts are directed to implementing anti-inflammatory therapeutic strategies across a growing number of CVDs, through repurposing of available anti-inflammatory drugs and development of novel anti-inflammatory compounds, which are herein concisely discussed. This review also summarizes the main characteristics and findings of completed and upcoming randomized controlled trials directly targeting inflammation in CVDs, and discusses major challenges and future perspectives in the exciting and constantly expanding landscape of cardioimmunology.
9Novel directions in inflammation as a therapeutic target in atherosclerosis.PubMed
Simone L Verweij, Fleur M van der Valk, Erik S G Stroes
PURPOSE OF REVIEW: Atherosclerosis is a chronic disease of the arterial wall largely driven by inflammation; hence, therapeutics targeting inflammatory pathways are considered an attractive strategy in atherosclerotic cardiovascular disease (ASCVD). The purpose of this review is to describe the randomized, placebo-controlled clinical trials currently investigating the impact of anti-inflammatory strategies in ASCVD patients, to discuss novel insights and targets into the role of innate immunity in atherosclerosis and to address the promise of local drug delivery as opposed to systemic therapies in atherosclerotic disease. RECENT FINDINGS: The first clinical trials using systemic anti-inflammatory drugs in ASCVD patients might be able to strengthen the case for immunomodulation once showing an improved ASCVD outcome. Several specific targets in innate immunity bear therapeutic potential, of which some have already entered the clinical arena. To prevent immunosuppression by systemic effects, drug delivery systems are increasingly being applied to locally attenuate plaque inflammation. SUMMARY: Anti-inflammatory therapies seem promising for future treatment of ASCVD. In view of the risk of immunosuppression in case of long term and systemic use of anti-inflammatory drugs, there is a clinical need for highly selective and targeted therapies in patients with atherosclerosis.
10Darapladib.PubMed
Quang T Bui, Robert L Wilensky
IMPORTANCE OF THE FIELD: Atherosclerosis is an inflammatory-immune mediated disease process. Plaque rupture is responsible for the clinical events of ischemic death, myocardial infarction, acute coronary syndromes and ischemic strokes. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) seems to play a major role in the development of such high-risk lesions, in both the coronary and carotid arteries. Darapladib is a selective inhibitor of Lp-PLA(2). AREAS COVERED IN THIS REVIEW: An overview of darapladib by reviewing the studies (1990 - 2009) that have provided the rationale for the development of darapladib; and a discussion of its potential merit as a new therapeutic drug to target high-risk atherosclerosis. WHAT THE READER WILL GAIN: The reader should gain an understanding of the importance of inflammation during atherogenesis as well as of the biology of Lp-PLA(2) and its proatherogenic role. Additional insights will be gained into the role of selective inhibitors of Lp-PLA(2) as new therapeutic agents. TAKE HOME MESSAGE: Darapladib is a selective inhibitor of Lp-PLA(2) and represents a new class of therapeutic agents that target inflammation to treat high-risk atherosclerosis.
11Efficacy and safety of inclisiran versus PCSK9 inhibitor versus statin plus ezetimibe therapy in hyperlipidemia: a systematic review and network meta-analysis.PubMed
Shengxuan Zhang, Lei Sun, Xinyu Xu, et al.
OBJECTIVE: Hyperlipidemia plays a crucial role in increasing the risk of cardiovascular diseases such as atherosclerosis. Recent studies have established that inclisiran positively influences lipid regulation. Nevertheless, its effectiveness in comparison to conventional treatments is still questionable. Hence, a methodical assessment of its effectiveness and safety is required. This research evaluates the efficacy and safety of inclisiran, PCSK9 inhibitors, and the combination of statins with ezetimibe in the treatment of hyperlipidemia via a network meta-analysis of randomized controlled trials (RCTs). METHODS: We performed an extensive search of English-language publications in the PubMed, Medline, Embase, and Cochrane Library databases until April 2024. We conducted a web-based meta-analysis and reported in accordance with the guidelines. We selected the percentage change in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) as efficacy evaluation metrics and the incidence of adverse events as safety evaluation metrics for analysis and comparison. RESULT: We incorporated 33 studies involving 23,375 patients, evaluating three interventions regarding their effects on LDL-C, TC, TG, HDL-C, and adverse events. All treatments improved metrics over placebo. Inclisiran significantly reduced LDL-C compared to statins (mean - 15.21, 95% CI [-25.19, -5.23]) but showed no significant difference from statin + ezetimibe. Surface under the cumulative ranking curve (SUCRA) rankings placed inclisiran highest for LDL-C reduction (26.2%). The combination of statin and ezetimibe was the most efficacious for triglyceride reduction (mean 17.2, 95% CI [10.22, 24.19]; mean 15.61, 95% CI [16.87, 24.35]). The safety profiles were comparable across treatments. CONCLUSION: Inclisiran with its superior LDL-C reduction and low frequency of administration, appears promising for hyperlipidemia treatment, particularly for patients with adherence issues or side effects from other medications. SYSTEMATIC REVIEW REGISTRATION: CRD42024550852.
12Long-term trials of colchicine for secondary prevention of vascular events: a meta-analysis.PubMed
Michelle Samuel, Colin Berry, Marie-Pierre Dubé, et al.
BACKGROUND AND AIMS: Colchicine has emerged as a safe and inexpensive anti-inflammatory medication to target the residual risk of cardiovascular events in the secondary prevention of coronary artery disease. Two recently published randomized controlled trials (RCTs) investigating colchicine in the post-stroke and post-myocardial infarction (MI) populations warrant a re-evaluation of colchicine. New evidence was synthesized in a systematic review and meta-analysis to determine the long-term efficacy and safety of colchicine for the secondary prevention of vascular disease. METHODS: Randomized controlled trials comparing the incidence of cardiovascular events between patients with clinically manifest vascular disease randomized to colchicine vs. placebo and ≥12-month follow-up were included. The primary efficacy endpoint is major adverse cardiovascular events (MACE) and includes cardiovascular mortality, MI, ischaemic stroke, and urgent coronary revascularization. The DerSimonian and Laird random effects model was used to calculate pooled effect estimates. RESULTS: Six RCTs, with a pooled sample size of 21 800 patients, were included (colchicine n = 10 871; placebo n = 10 929). Over a follow-up of 12-34 months, colchicine reduced the incidence of MACE compared with placebo [pooled hazard ratio .75, 95% confidence interval (CI) .56-.93]. The reduction in cardiovascular events among colchicine patients was driven by reductions in MIs, ischaemic strokes, and urgent coronary revascularizations (P < .05 for all). No differences were detected for safety outcomes (P > .05 for all), including non-cardiovascular deaths (risk ratio 1.08, 95% CI .76-1.54). CONCLUSIONS: This updated meta-analysis of RCTs demonstrated a substantial reduction in MACE, MI, ischaemic stroke, and recurrent coronary revascularization with colchicine compared with placebo. Therefore, the results support the use of colchicine to reduce recurrent cardiovascular events.
13Lipoproteins for therapeutic delivery: recent advances and future opportunities.PubMed
Sangram Raut, Jean-Louis Dasseux, Nirupama A Sabnis, et al.
The physiological role(s) of mammalian plasma lipoproteins is to transport hydrophobic molecules (primarily cholesterol and triacylglycerols) to their respective destinations. Lipoproteins have also been studied as drug-delivery agents due to their advantageous payload capacity, long residence time in the circulation and biocompatibility. The purpose of this review is to briefly discuss current findings with the focus on each type of formulation's potential for clinical applications. Regarding utilizing lipoprotein type formulation for cancer therapeutics, their potential for tumor-selective delivery is also discussed.
14Multi-omics and experimental validation reveal the mechanism of DanxiaTiaoban decoction in treating atherosclerosis.PubMed
Yirong Ma, Miao Hu, Junyu Lai, et al.
BACKGROUND: Atherosclerosis (AS) is a leading risk factor for cardiovascular diseases globally, characterised by the accumulation of lipids and cholesterol in arterial walls, causing vascular narrowing and sclerosis along with chronic inflammation; this leads to increased risk of heart disease and stroke, significantly impacting patients' health. Danxia Tiaoban Decoction (DXTB), a traditional Chinese medicine (TCM) formula, has demonstrated positive clinical effects in treating AS; however, its mechanisms of action remain unclear. OBJECTIVE: To explore the potential mechanisms of action of DXTB in treating AS through multi-omics integration and experimental validation. METHOD: Active components of DXTB and their targets were identified using the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP), Batman, Herb, and TCM Integrated Database (TCMID). The compounds most closely associated with the active ingredients in DXTB were identified using ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLCHRMS). In addition, targeted quantification of quercetin, luteolin and alisol C in DXTB and in mouse serum collected 2 h after high-dose oral gavage was performed using high-performance liquid chromatography-triple quadrupole tandem mass spectrometry (LC-QQQ-MS/MS). By analysing deCODE plasma protein quantitative trait loci (pQTL) data and multiple Gene Expression Omnibus (GEO) datasets, proteins and differentially expressed genes (DEGs) associated with AS were identified. Twelve machine learning algorithms were employed to select core genes, which were then evaluated using nomogram and shapley additive explanations (SHAP) values to assess their effect on disease risk and model outputs. A drug-component-target network was constructed to identify the core active components of the drug. Mendelian randomization (MR) analysis was used to verify the causal relationship between core genes and AS, while molecular docking and molecular dynamics (MD) simulations were employed to evaluate interactions between DXTB active components and target proteins, which were validated using surface plasmon resonance (SPR) experiments. Additionally, AS was induced in Apolipoprotein E gene knockout (ApoE) mice fed with high-fat diet and treated with low, medium, and high doses of DXTB by gavage. Aortic tissue pathological changes were examined using haematoxylin and eosin (H&E) staining, transmission electron microscopy (TEM), and Oil Red O staining. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot were used to verify the expression of core genes and the activation of core pathways, and changes in inflammatory factor levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: A total of 51 common target genes associated with DXTB and AS were identified, primarily enriched in the lipid and AS and Fc epsilon RI (FcεRI) signalling pathways, with the p38 mitogen-activated protein kinase (MAPK) signalling pathway potentially serving as the key mechanism by which DXTB regulates AS. Six core genes-colony-stimulating factor 1 receptor (CSF1R), dipeptidyl peptidase 4 (DPP4), neutrophil cytosol factor 1 (NCF1), matrix metalloproteinase-9 (MMP9), integrin alpha l (ITGAL), and LYN proto-oncogene (LYN)-were selected using machine learning algorithms. A multivariate logistic regression model was constructed based on these core genes, and their specific contributions and diagnostic value were demonstrated through SHAP value analysis and Nomogram, highlighting the model's potential in enabling clinical decision-making. MR analysis further suggested a causal relationship between CSF1R and AS risk. The AddModuleScore analysis indicated that core gene set expression and MAPK signalling pathway are particularly active in monocytes. Molecular docking, MD simulations, and SPR collectively confirmed a pronounced binding affinity between the active constituents and the core targets, consistent with results from network pharmacology and machine learning analyses. LC-QQQ-MS/MS quantification corroborated these findings by confirming measurable systemic exposure of the core constituents at 2 h post-dose. Furthermore, animal experiments showed that DXTB reduced lipid accumulation, inhibited activation of p38 MAPK signalling pathway, regulated the expression of core genes, and decreased inflammatory factors interleukin (IL)-1β, IL-6, and tumour necrosis factor (TNF)α, leading to reduced plaque area. CONCLUSION: This study innovatively integrates multi-omics analyses, advanced machine learning algorithms, and rigorous experimental validation to systematically elucidate the therapeutic mechanisms of DXTB in the treatment of AS. Our findings demonstrate for the first time that DXTB may exert its therapeutic effects by modulating key inflammation- and lipid-associated pathways, particularly the p38 MAPK signalling pathway, as well as core genes including CSF1R, DPP4, and MMP9. In addition, DXTB may alleviate vascular inflammation and lipid accumulation by inhibiting the differentiation of monocytes into macrophages and their subsequent transformation into foam cells. The integrated approach combining bioinformatics with experimental validation provides strong support for the potential clinical efficacy of DXTB and identifies novel candidate targets for AS therapy. These insights enhance the current understanding of DXTB's mechanisms of action and offer a valuable reference for future research and therapeutic development in cardiovascular disease.
15Comparative Efficacy of Nonstatin Lipid-Lowering Therapies in Patients With Hypercholesterolemia at Increased Cardiovascular Risk: An Updated Network Meta-Analysis.PubMed
Heather Burnett, Allie Cichewicz, Harshul Natani, et al.
Hypercholesterolemia is associated with atherosclerotic cardiovascular disease (ASCVD), a leading cause of morbidity and mortality. Nonstatin lipid-lowering therapies (LLTs) such as ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs), bempedoic acid, and inclisiran have been recommended in clinical guidelines to treat patients with ASCVD and/or high cardiovascular (CV) risk having elevated low-density lipoprotein cholesterol (LDL-C) despite being treated with maximally tolerated doses (MTD) of statins. Our previously published network meta-analysis (NMA) 1 was updated in this study to evaluate comparative efficacy of nonstatin LLTs in reducing LDL-C among patients with ASCVD and/or high CV risk receiving MTD statins. The systematic literature review previously conducted to inform our NMA was updated through January 2023, wherein more recent clinical trials of nonstatin LLTs (ORION-15, ORION-18, and HUA TUO) and additional data on monthly dosing regimens for PCSK9 mAbs were included. The outcome of interest was percentage change in LDL-C at week 24. Random-effects Bayesian NMA was performed. Comparative efficacy was estimated as mean difference (MD) with 95% credible intervals (CrIs). A total of 20 trials were deemed relevant for the NMA. Consistent with the previous findings from our NMA, this study demonstrated that inclisiran provided superior efficacy in LDL-C lowering compared with ezetimibe and bempedoic acid (MD: -44.24 [95% CrI: -51.84 to -36.70]). This NMA further reaffirmed that inclisiran provided comparable LDL-C reduction versus alirocumab (MD: -1.93% [95% CrI: -8.56 to 4.20]) and evolocumab (MD: 2.00% [95% CrI: -4.58 to 8.60]) among patients with ASCVD and/or high CV risk on MTD statins.
16Novel Antiatherosclerotic Therapies.PubMed
Peter Libby, Brendan M Everett
Many measures can control lipid risk factors for atherosclerosis. Yet, even with excellent control of dyslipidemia, other sources of risk remain. Hence, we must look beyond lipids to address residual risk. Lifestyle measures should form the foundation of cardiovascular risk control. Many pharmacological interventions targeting oxidation have proven disappointing. A large program tested inhibition of a LpPLA (lipoprotein-associated phospholipase A), culminating in 2 large-scale clinical trials that did not meet their primary end points. A variety of antioxidants have not shown benefit in clinical trials. Numerous laboratory and clinical studies have inculpated inflammatory pathways in the pathogenesis of atherosclerotic events. The p38 MAPK (mitogen-activated protein kinase) inhibitor losmapimod and an inhibitor of a leukocyte adhesion molecule, P-selectin, did not alter adverse events in trials. Low-dose methotrexate, despite the promising observational studies, did not lower biomarkers of inflammation or alter cardiovascular outcomes in the CIRT (cardiovascular inflammation reduction trial). Four large-scale investigations underway will determine colchicine's ability to reduce recurrent events in secondary prevention. The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) showed that an antibody that neutralizes IL (interleukin)-1β can reduce recurrent cardiovascular events in secondary prevention. The success of CANTOS points to the pathway that leads from the NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) inflammasome through IL-1β to IL-6 as an attractive target for further study and clinical development beyond lipid therapies to address the unacceptable burden of risk that remains despite our best current care in secondary prevention.
17Materials technology in drug eluting balloons: Current and future perspectives.PubMed
Gordon Minru Xiong, Huiying Ang, Jinjie Lin, et al.
The coating material technology is important for the delivery of anti-proliferative drugs from the surface of drug-eluting balloons (DEBs), which are emerging as alternatives to drug-eluting stents (DES) in the field of interventional cardiology. Currently, several shortcomings limit their competition with DES, including low drug transfer efficiency to the arterial tissues and undesirable particulate generation from the coating matrix. In this review, we provide a survey of the materials used in existing DEBs, and discussed the mechanisms of actions of both the drugs and coating materials. The type of drug and the influence of the coating material characteristics on the drug uptake, distribution and retention in arterial tissues are described. We also summarize the novel coating excipients under development and provide our perspective on the possible use of nano-scale carriers to address the shortcomings of current coating technology. The scope of this review includes only materials that have been approved for biomedical applications or are generally recognized as safe (GRAS) for drug delivery.
18New Drugs for Atherosclerosis.PubMed
Caroline S Bruikman, Robert M Stoekenbroek, G Kees Hovingh, et al.
Atherosclerosis, the underlying process that ultimately leads to clinical cardiovascular disease (CVD), is caused by the multifactorial interaction of various conditions, and dyslipidemia is widely acknowledged as 1 of the crucial risk factors in this process. Statin drugs have been shown to decrease low-density lipoprotein cholesterol and CVD morbidity as well as mortality and are therefore pivotal in CVD prevention. Despite the use of statin drugs, CVD remains a leading cause of mortality worldwide, which suggests that additional lipid-lowering therapies are warranted. Several novel therapeutic agents, which are described in this review, are now well on their way in their respective development paths and might revolutionize anti-atherosclerotic drug therapy.
19Nucleic Acid-Based Therapies for Atherosclerosis.PubMed
Petri Mäkinen, Anna-Kaisa Ruotsalainen, Seppo Ylä-Herttuala
PURPOSE OF REVIEW: Atherosclerosis is characterized by accumulation of lipids and chronic inflammation in medium size to large arteries. Recently, RNA-based antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are being developed, along with small molecule-based drugs and monoclonal antibodies, for the treatment of risk factors associated with atherosclerosis.. The purpose of this review is to describe nucleic acid-based therapeutics and introduce novel RNAs that might become future tools for treatment of atherosclerosis. RECENT FINDINGS: RNA-based inhibitors for PCSK9, Lp(a), ApoCIII, and ANGPTL3 have been successfully tested in phase II-III clinical trials. Moreover, multiple microRNA and long non-coding RNAs have been found to reduce atherogenesis in preclinical animal models. Clinical trials especially with ASOs and siRNAs directed to liver, targeting cholesterol and lipoprotein metabolism, have shown promising results. Additional research in larger patient cohorts is needed to fully evaluate the therapeutic potential of these new drugs.
20High-Density Lipoprotein-Targeted Therapy and Apolipoprotein A-I Mimetic Peptides.PubMed
Yoshinari Uehara, Giulia Chiesa, Keijiro Saku
Numerous randomized clinical trials have established statins as the major standard therapy for atherosclerotic diseases because these molecules decrease the plasma level of low-density lipoprotein (LDL) cholesterol and moderately increase that of plasma high-density lipoprotein (HDL) cholesterol. The reverse cholesterol transport pathway, mediated by HDL particles, has a relevant antiatherogenic potential. An important approach to HDL-targeted therapy is optimization of the HDL-cholesterol level and enhanced removal of plasma cholesterol, together with the prevention and mitigation of inflammation related to atherosclerosis. Small-molecule inhibitors of cholesteryl ester transfer protein (CETP) increase the HDL-cholesterol level in subjects with normal or low HDL-cholesterol. However, CETP inhibitors do not seem to reduce the risk of atherosclerotic diseases. HDL therapies using reconstituted HDL, including apolipoprotein (Apo) A-I Milano, ApoA-I mimetics, or full-length ApoA-I, are dramatically effective in animal models. Of those, the ApoA-I-mimetic peptide called FAMP effectively removes cholesterol via the ABCA1 transporter and acts as an antiatherosclerotic agent by enhancing the biological functions of HDL without elevating the HDL-cholesterol level. Our review of the literature leads us to conclude that HDL-targeted therapies have significant atheroprotective potential and thus may effectively treat patients with cardiovascular diseases.