Lead
The 92nd Annual Meeting of the European Society of Atherosclerosis (EAS2024) is being held in Lyon, France, presenting many of the latest advances in basic, translational and clinical research on atherosclerosis and related vascular diseases. Among them, lipoprotein(a) [Lp(a)] has been one of the potential new targets of lipid intervention with more evidence and attention in recent years, and a large number of research results have been published in the EAS2024. What are the key findings of these studies? What are the implications? This article selects some researches, let's take a look!
One
Why focus on Lp(a)? The relationship between increased LP(a) and cardiovascular risk has been re-emphasized
Low-density lipoprotein cholesterol (LDL-C) is well known as the primary target for lipid intervention in atherosclerotic cardiovascular disease (ASCVD). However, even with LDL-C level control, there is still a residual risk of cardiovascular events [1]. A series of studies suggest that there are new lipid markers associated with residual risk, and Lp(a) is one of them. In recent years, multidimensional studies have consistently found that Lp(a) is a pathogenic risk factor for ASCVD independent of LDL-C [2]. The Chinese Guidelines for the Management of Lipids (2023) clearly state that the vast majority of current studies support Lp(a) as an independent risk factor for ASCVD and calcific aortic stenosis [3]. Lp(a) has been reconfirmed as an independent risk factor in EAS2024 recent study.
01
High Lp(a) is independently associated with subclinical carotid atherosclerosis (CA) in asymptomatic populations
A German study [4] enrolled 7482 subjects who had been tested for Lp(a) and did not have ASCVD at the time of enrollment from the population-based Hamburg Urban Health Study based on Lp(a) risk-related cut-offs (<75 nmol/L, 75~).
The results showed that the median Lp(a) in this population was 17.7 nmol/L, and 36.3% had subclinical CA, which was more common in the high Lp(a) group, and was used in Lp(a) < 75 nmol/L, 75~, and independent of traditional cardiovascular risk factors and lipid-lowering drugs. The corresponding OR of Lp(a) 75~<125 nmol/L was 1.17 (95%CI: 0.95~1.43, P=0.14) (Fig. 1). It can be seen that in asymptomatic populations, high Lp(a) levels are independently associated with subclinical CA, suggesting that Lp(a) can be used as an early indicator of atherosclerotic burden in the general population.
Figure 1. Relationship between continuous Lp(a) levels and subclinical CA
02
Lp(a) is independently associated with the risk of ischemic stroke (IS) and its large atherosclerosis subtype
A prospective case-control study in Slovakia [5] investigated the relationship between serum Lp(a) levels and the risk of IS and its subtypes in 231 patients with acute IS (case group) and 163 age- and sex-matched subjects (control group).
结果显示，病例组Lp(a)水平显著高于对照组[81.81 nmol/L vs. 59.75 nmol/L，P=0.036]，且按四分位分层的Lp(a)水平与IS风险有关{Q1 [Lp(a)117 nmol/L]：OR 2.23，95%CI：1.23~4.03，P=0.008}。 基于IS TOAST分型的亚组分析显示，与对照组相比，Lp(a)>75 nmol/L（30 mg/dl）与大动脉粥样硬化型IS风险显著相关（OR 2.34，95%CI：1.39~3.93，P=0.001），但与其他IS亚型无相关性（图2）。 即使校正IS已知危险因素后，Lp(a)的影响仍然显著（总体：OR 1.99，95%CI：1.05~3.76，P=0.04；大动脉粥样硬化亚型：OR 2.54，95%CI：1.39~4.67，P=0.003）。 研究者总结，Lp(a)是IS及其大动脉粥样硬化亚型的独立危险因素。
Figure 2. The relationship between Lp(a)>75 nmol/L and the risk of different IS subtypes
Crypto,i.e., athero, an athero, an athero, osso. But it's not a bad one.
03
30≤Lp(a)<50 mg/dl can be used as predictors of ASCVD risk
A study was conducted by Russian scholars [6] to determine the Lp(a) threshold for ASCVD in different vascular beds. In this study, 898 adult patients who underwent imaging in three vascular beds (coronary, carotid, and lower extremity arteries) and had an Lp(a) < 50 mg/dl were divided into group I based on Lp(a) levels [Lp(a)
The results showed that the two groups were comparable in terms of gender, incidence of hypertension, smoking status, type 2 diabetes mellitus, and blood lipid levels. Compared with group I., the incidence of myocardial infarction, carotid artery and lower extremity atherosclerosis was higher in group II. There was no significant difference in the incidence of coronary artery disease and IS between the two groups (Figure 3). Therefore, 30≤Lp(a)<50 mg/dl is associated with myocardial infarction and atherosclerosis of the carotid artery and lower extremities.
图3. 30≤Lp(a)<50 mg/dl相比Lp(a)
The threshold for increasing the risk of Lp(a) varies among different ethnicities, and the recommendations of guidelines and consensus in different countries are also inconsistent. The 2022 EAS Lp(a) consensus [7] recommends that clinical guidelines should consider using "gray" area risk thresholds (30~50 mg/dl or 75~125 nmol/L) rather than absolute values to determine (≥ 50 mg/dl; 125 nanomol/L) or exclusion (30 mg/dl increases cardiovascular risk, and the risk increases further with increasing Lp(a) levels.
Two
Adults should be tested at least once in their lifetime for Lp(a), but there are many challenges to testing
Lipid profiles are the basis for detecting dyslipidemia, assessing ASCVD risk, and determining intervention strategies. Because individual plasma Lp(a) levels are primarily genetically determined, they remain relatively stable throughout their lives [2]. The 2022 EAS Lp(a) consensus [7] recommends that adults should be tested at least once for Lp(a) to identify those at high cardiovascular risk; Screening for Lp(a) is recommended in young adults with a history of IS, a family history of early-onset ASCVD, and high Lp(a) without other identifiable risk factors; Perform Lp(a) cascade screening in patients with familial hypercholesterolemia (FH), a family history of very high Lp(a), or a history of ASCVD. The Chinese Guidelines for the Management of Lipids (2023) [3] also recommend that at least one Lp(a) test should be included in the lipid profile of adults and high-risk individuals for ASCVD.
However, laboratory testing for Lp(a) is still not standardized, resulting in a lack of accurate assessment of the association between Lp(a) and CVD [2]. Challenges remain in the diagnosis of LP(A), including lack of standardization of reporting, limitations of batch analysis, and variability in interpretation. EAS2024 previous Colombian study, the standardization of Lp(a) testing was investigated [8]. In Colombia, the Lp(a) test has been covered by health insurance for patients with recurrent acute coronary syndromes and/or early-onset CVD. The study looked at 11 clinical laboratories, six of which outsourced samples to other laboratories located in the capital; The selection of detection techniques was evenly distributed, with 5 laboratories using scattering nephelometry and 6 laboratories using immunotransmission nephelodimetry. The primary reporting method was mg/dl (reference value 30 mg/dL) and only 2 laboratories used nmol/L (reference value 75 nmol/L).
From the results of this study, it can be seen that the Lp(a) test lacks national standardization in Colombia and cannot meet the requirements of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCCLM). Similar problems also exist in China, although in recent years, with the release of relevant guidelines and consensus, the clinical attention to Lp(a) has gradually increased, but most patients and even some doctors still have insufficient understanding of Lp(a). In view of the polymorphism of Lp(a), there is still a lack of a unified national standard for laboratory testing. Therefore, how to improve the awareness level of Lp(a) and gradually promote the standardization and popularization rate of Lp(a) testing needs to be further explored in the future.
Three
How should patients with elevated Lp(a) be managed? Pharmacological intervention, where is the way forward?
The core principle of the management of patients with elevated LP(A) is to reduce the overall risk of ASCVD, including the control of the various concomitant clinically significant dyslipidemias [2]. The Chinese Guidelines for the Management of Blood Lipids (2023) [3] recommend high Lp(a) as a management indicator for patients at high risk of ASCVD (II.a, C). However, to date, there is no effective treatment for lowering Lp(a), and no drug has been approved specifically for lowering Lp(a).
01
Statin therapy has limited ability to lower Lp(a) and may increase Lp(a)
Some patients with elevated Lp(a) may benefit from more aggressive statin-lowering LDL-C therapy, although statin therapy has also been shown to be mildly elevated Lp(a) [9]. EAS2024 the previous Japanese study [10], 371 patients who received lipid-lowering therapy were tested for Lp(a) levels at 3 months, 6 months, and 1 year after treatment, respectively. The results showed that there was no change in Lp(a) levels after 1 year of treatment with pitavastatin and ezetimibe, but increased Lp(a) after treatment with atorvastatin and rosuvastatin. Rosuvastatin significantly increased Lp(a) levels compared with pitavastatin (+5.1% vs. -1.2%, P<0.05) (Table 1). In the opinion of the investigators, if an increase in Lp(a) is observed after a statin treatment, switching to a different statin may be necessary.
Table 1. Lipid profile at baseline and at 1 year of treatment
02
New Lp(a)-lowering drugs have therapeutic potential and are expected to benefit a large number of ASCVD patients
Among the existing lipid-lowering drugs, P9 target drugs showed a certain Lp(a) reduction effect. For example, the small interfering RNA (siRNA) drug that targets PCSK9 mRNA can reduce Lp(a) levels by about 20%~30% [11]. In addition, among the new drugs under development, small nucleic acid drugs are the most promising to be approved for lowering Lp(a). Among them, Pelacarsen is the first antisense oligonucleotide (ASO) drug to reduce Lp(a), which significantly reduces Lp(a) by targeting Apo(a) synthesis and has been granted Breakthrough Therapy Designation by the CDE in China [12].
So, how high is the clinical need for Lp(a)-lowering therapy? This was explored EAS2024 a previous Italian real-world study [13]. The researchers collected data from 5961 patients from dyslipidemia clinics, including 5089 and 872 for primary and secondary prevention of ASCVD. The results showed that except for familial hypertriglyceridemia, the Lp(a) level of patients with other types of ASCVD was significantly increased (P<0.05). Compared with the primary prevention of ASCVD, Lp(a) 50~70 mg/dl (7.3% vs. 4.3%), P70 mg/dl (47.4% vs. 3.1%, P<0.05) patients were more likely to receive secondary prophylaxis, while patients with Lp(a) 30~49 mg/dl were less likely to undergo secondary prophylaxis (1.2% vs. 12.1%, P Even if conservatively estimated, the prevalence of ASCVD with high Lp(a) is high. In these patients, there is a need for Lp(a) reduction. It is worth mentioning that the Phase 3 clinical trial HORIZON (NCT04023552) to explore the impact of Pelacarsen on cardiovascular outcomes in patients with elevated Lp(a) is underway, and its results are promising, which is expected to lead to breakthrough treatment options for Lp(a) reduction.
Table 2. Distribution of primary and secondary prevention of ASCVD in patients in different Lp(a) subgroups
Four
epilogue
A large body of evidence suggests that elevated Lp(a) is an independent risk factor for a variety of cardiovascular and cerebrovascular diseases. Both domestic and foreign guidelines/consensus recommend that adults be tested at least once in their lifetime for Lp(a). However, there are many challenges in the detection and management of LP(a), which need to be improved and paid attention to urgently. Although the adverse effects of Lp(a) are well known, specific therapies are lacking. Cardiovascular outcome studies of new Lp(a)-lowering drugs, such as Pelacarsen's HORIZON, are currently underway, and it is expected that they can bring significant clinical benefits to patients with ASCVD with elevated Lp(a).
bibliography
1. Sabatine MS, et al. N Engl J Med. 2017; 376(18): 1713-1722.
2. Beijing Cardiology Society. Chinese Journal of Circulation. 2021; 36(12): 1158-1167.
3. Joint Expert Committee on the Revision of Chinese Guidelines for the Management of Blood Lipids. Chinese Journal of Circulation. 2023; 38(3): 237-271.
4. Arnold N, et al. 078 - LIPOPROTEIN(A) AND SUBCLINICAL CAROTID ATHEROSCLEROSIS: RESULTS FROM THE POPULATION-BASED HAMBURG CITY HEALTH STUDY (HCHS) (ID 403). 92nd EAS Congress, 26-29 May, 2024.
5. Lackova A, et al. 091 - ASSOCIATION OF SERUM LIPOPROTEIN (A) LEVELS TO ISCHEMIC STROKE RISK (ID 776). 92nd EAS Congress, 26-29 May, 2024.
6. Tmoyan NA, et al. 098 - LIPOPROTEIN(A) LEVEL BELOW 50 MG/DL AS A PREDICTOR OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASES (ID 1184). 92nd EAS Congress, 26-29 May, 2024.
7. Kronenberg F, et al. Eur Heart J. 2022; 43(39): 3925-3946.
8. Roman-González A, et al. 093 - LP(A) MEASUREMENT IN COLOMBIA: OPPORTUNITIES TO STANDARDIZE ITS RESULTS (ID 720). 92nd EAS Congress, 26-29 May, 2024.
9. Yeang C, et al. J Clin Lipidol. 2016; 10(3): 594-603.
10. Tsuda S, et al. 100 - IMPACT OF LIPID LOWERING DRUGS ON LIPOPROTEIN (A) IN PATIENTS WITH ATHEROSCLEROTIC DISEASE (ID 443). 92nd EAS Congress, 26-29 May, 2024.
11. Ray KK, et al. N Engl J Med. 2020; 382(16): 1507-1519.
12.https://www.cde.org.cn/main/xxgk/listpage/da6efd086c099b7fc949121166f0130c
13. Cicero AFG, et al. 172 - ESTIMATING PREVALENCE AND CHARACTERISTICS OF PATIENTS POTENTIALLY ELIGIBLE FOR LIPOPROTEIN(A)-LOWERING THERAPIES IN A REAL-WORLD SETTING (ID 143). 92nd EAS Congress, 26-29 May, 2024.
The approval code TQJ0025224-61236, valid until 2025-05-29, the information expires and is deemed invalid