Lipoprotein (a) and cerebrovascular disease

Abstract

The role of lipoprotein (a) [Lp(a)] in cerebrovascular disease is a topic of importance. In this narrative review, pertinent studies have been leveraged to comprehensively examine this relationship from diverse perspectives.

Lp(a) shares structural traits with low-density lipoprotein cholesterol. Lp(a) is synthesized by hepatocytes, and its plasma levels are genetically determined by the LPA gene, which produces apolipoprotein (a).

Numerous epidemiological studies have confirmed the positive correlation between elevated serum Lp(a) levels and the occurrence or recurrence of cerebrovascular events, especially ischemic strokes, in adults. It should be noted that the correlation strength varies among studies and is marginal in Mendelian randomization studies.

Regarding pediatric patients, screening is currently limited to those with a relevant medical history. Lp(a) seems to play a significant role in the pathogenesis of arterial ischemic stroke in children because environmental thrombotic and atherogenic factors are generally not present.

Phase 3 trials of novel Lp(a) targeting agents, such as pelacarsen and olpasiran, are anticipated to demonstrate their efficacy in reducing the incidence of stroke. Given the richness of the literature, new guidelines regarding Lp(a) screening and management in targeted populations are warranted to provide more effective primary and secondary prevention.

Introduction

Lipoprotein (a) [Lp(a)] constitutes an intriguing lipoprotein class currently under intense scrutiny in modern scientific research. Lp(a) is synthesized and secreted by hepatocytes and shares similarities with low-density lipoprotein, as both consist of an apolipoprotein B-100 (apoB-100) molecule encircling a cholesterol ester core. However, in the case of Lp(a), apoB-100 is tethered to a polymorphic glycoprotein named apolipoprotein (a) [apo(a)]. Lp(a) exhibits remarkable size heterogeneity and is derived from the diverse LPA gene, which exhibits numerous polymorphisms and genetic variants. ¹ Plasma Lp(a) levels are predominantly determined by the genetic makeup at the LPA gene locus and the related apo(a) synthesis rate and remain unaffected by dietary or environmental factors. Smaller isoforms of LPA are linked to an increased apo(a) synthesis rate and high plasma Lp(a) levels.^2,3

Plasma Lp(a) levels may range from less than 1 mg/dL to more than 1000 mg/dL, but the cutoff values for hyperlipoproteinemia (a) are 30 mg/dL and 50 mg/dL in the US and Europe, respectively. It should be noted that although cutoff values for Lp(a) have been proposed by several organizations, a general consensus has not been reached. Mounting evidence suggests that Lp(a) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), and elevated plasma Lp(a) levels are causally and independently linked to an increased probability of developing cardiovascular disease (CVD). Apo(a) is the key factor responsible for the atherogenic, thrombogenic, and proinflammatory properties of Lp(a). Its unique structure resembles that of plasminogen. Lp(a) facilitates proinflammatory interactions, assists in binding oxidized phospholipids, and promotes inhibition of fibrinolysis and platelet aggregation. Despite numerous attempts to reduce Lp(a) levels pharmacologically with various success rates, there are currently no medications approved specifically for hyperlipoproteinemia (a) treatment. Nevertheless, promising potential exists for novel Lp(a)-targeting therapeutic agents.^3–6 Regarding Lp(a) level measurement in adults, the European Atherosclerosis Society 2022 consensus statement for Lp(a) advocates for at least one assessment during a lifetime to enhance cardiovascular risk prediction and stratification. In youth, screening is particularly advised when there is a parental history of ischemic stroke or premature ASCVD with no other identifiable risk factors.^4,7

Many scientific studies have focused on the correlation of Lp(a) levels with coronary heart disease ⁸ as well as peripheral arterial disease.^9,10 Regarding the documentation of the role of Lp(a) levels in the development of cerebrovascular disease, the updated revision and clinical modification of the International Classification of Diseases system, ICD-10-CM, classifies cerebrovascular accidents or “stroke” as follows: ischemic stroke, intracerebral hemorrhage (ICH), subarachnoid hemorrhage, and transient ischemic attack (TIA). ¹¹ In this context, the Emerging Risk Factors Collaboration gathered records involving 126,634 participants in 36 prospective studies with 1.3 million person-years of follow-up and, after making appropriate adjustments for age, sex, lipids, and other conventional risk factors, found that each 3.5-fold increase in the Lp(a) level was associated with a 10% increased risk for ischemic stroke and a 6% increased risk for hemorrhagic stroke. ¹² A meta-analysis from 2021 included 41 studies involving 7874 ischemic stroke patients and 32,138 controls [13 studies of ischemic stroke subtypes based on the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification] and 7 studies with ICH patients and 2865 control subjects. The results demonstrated statistically significant associations of elevated Lp(a) levels with ischemic stroke, especially the large artery atherosclerosis ischemic stroke subtype, and ICH (standardized mean difference: 0.76, 0.68, and 0.65, respectively). ¹³

This narrative review presents epidemiological and clinical evidence pertaining to the effects of Lp(a) on cerebrovascular disease in adult and pediatric patients. The reader is kindly reminded to exercise caution when interpreting the results. Cited studies in this article use different cutoff values for Lp(a) and different units such as mg/dL, nmol/L, and μg/mL in their results. Although the preferable unit of measurement for Lp(a) is nmol/L, the results are reported in different units—mainly in mg/dL—in the original studies. To our knowledge, there is no exact formula available to convert mg/dL into nmol/L for Lp(a); therefore, the units are presented exactly as originally stated. In addition, standardized assays for Lp(a) may not have been used in older studies.

Methods

The current narrative review is based on evidence gathered from an extensive examination of existing literature. A thorough search of peer-reviewed journals was conducted using various key terms, including “lipoprotein(a)”, “cerebrovascular disease”, “ischemic stroke”, “treatments”, and “atherosclerosis”. Two online databases, PubMed and Google Scholar, were meticulously explored to identify meta-analyses, Mendelian randomization studies, observational studies, and clinical trials. Furthermore, the reference sections of each article were scrutinized to uncover additional relevant sources. Our search process yielded 63 articles through 2024.

Lp(a) and cerebrovascular accidents

According to the Global Stroke Fact Sheet 2022, stroke remains the second leading cause of death worldwide and the third leading cause of death and disability combined. During the course of 30 years, from 1990 to 2019, the burden of stroke increased by 70% for incident strokes, 102% for prevalent strokes, 43% for deaths from stroke, and 143% for disability-adjusted life years. The stroke burden resided mainly in lower and lower-to-middle income countries (86% of deaths and 89% of disability-adjusted life years). The lifetime risk has also increased to one in four people. The estimated global cost is US$ 891 billion. ¹⁴ In the US, more than 795,000 people suffer a stroke every year. Of these events, 610,000 are first time events, with 87% of all strokes being ischemic and the remaining 13% hemorrhagic. The total stroke-related cost between 2018 and 2019 was US$ 56.5 billion. ¹⁵ According to the TOAST classification, common mechanisms that lead to ischemic stroke include embolisms (cardioembolisms, artery-to-artery embolisms, and paradoxical embolisms), large vessel disease (atherosclerotic stenosis, occlusion, or artery dissection), small vessel disease, and other unidentifiable causes. ¹⁶

Lp(a) and ischemic stroke in adult patients

Systematic reviews and meta-analyses have demonstrated hyperlipoproteinemia (a) as an independent risk factor for ischemic stroke.^13,17,18 In fact, elevated Lp(a) levels seem to significantly influence the occurrence of ischemic stroke in adult patients younger than 55 years old. ¹⁸ A noteworthy association with the large artery atherosclerosis ischemic stroke subtype and, interestingly, with ICH, has also been observed. ¹³

Interethnic differences in Lp(a) and stroke

The Atherosclerosis Risk in Communities (ARIC) study followed 14,221 men and women, (3647 Black and 10,574 White participants) aged 45 to 64 years over the course of 13.5 years, during which 496 ischemic strokes occurred. A 79% higher age-, sex-, and race-adjusted rate ratio of ischemic stroke was observed in individuals with an Lp(a) level greater than or equal to 300 μg/mL (30 mg/dL) compared with those with an Lp(a) level below 100 μg/mL (10 mg/dL). The results further revealed that an elevated Lp(a) concentration ≥300 μg/mL was linked to an increased occurrence of ischemic stroke in both Black individuals and White women, but this association was not observed in White men [multivariate adjusted rate ratios: 1.84 (95% confidence interval [CI], 1.05–3.07) in Black women, 1.72 (95% CI 0.86–3.48) in Black men, 2.42 (95% CI 1.30–4.53) in White women, and 1.18 (95% CI 0.47–2.90) in White men]. ¹⁹ The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, which included 30,239 Black and White US adults aged 45 and older recruited between 2003 and 2007, aimed to explore regional and racial variations in stroke mortality. Baseline Lp(a) levels were measured in 572 patients with incident ischemic stroke and a 967-person cohort random sample. After adjusting for age, sex, and stroke risk factors, individuals in the fourth Lp(a) quartile showed a weak association with overall ischemic stroke, with a hazard ratio (HR) of 1.45 (95% CI 0.96–2.19). Racial differences were observed, with a stronger association between Lp(a) and ischemic stroke in Black (HR 1.96, 95% CI 1.10–3.46) than in White participants (HR 1.14, 95% CI 0.64–2.04). The links between stroke and Lp(a) were comparable in both sexes. This study suggests the need for further research to confirm the role of racial differences in the impact of Lp(a) as a risk factor for ischemic stroke. ²⁰

Relationship of Lp(a) level with stroke and impact of various risk factors

Mendelian randomization studies utilized data from large genome-wide association study databases to investigate the causal relationship between Lp(a) and stroke. A recent study found a marginal plausible causal relationship between genetically predicted Lp(a) and total stroke [odds ratio, OR (95% CI): 1.003 (1.001–1.006), p = 0.010], ischemic stroke [OR (95% CI): 1.004 (1.001–1.007), p = 0.004], and large artery atherosclerotic stroke [OR (95% CI): 1.012 (1.004–1.019), p = 0.002]. ²¹ Another Mendelian randomization analysis confirmed the causal relationship between elevated Lp(a) levels and large artery atherosclerotic stroke (OR = 1.003, 95% CI 1.002–1.004, p = 9.50E −11), whereas it failed to demonstrate a causal relationship between elevated Lp(a) levels and total ischemic stroke, small vessel stroke, or lacunar stroke. ²²

A study published in 2023 attempted to elucidate whether fibrinogen possesses a mediating role in the association between the Lp(a) level and ischemic stroke risk. The study involved 516 patients with ischemic stroke matched 1:1 with individuals without ischemic stroke based on age and sex. Subjects with ischemic stroke exhibited significantly higher Lp(a) levels than those without ischemic stroke (p < 0.001). Each standard deviation increase in the Lp(a) level was associated with a 27% higher risk of ischemic stroke (OR 1.27, 95% CI: 1.11–1.45). Fibrinogen played a mediating role, accounting for 10.15% of the association between Lp(a) and the risk of ischemic stroke. ²³ In addition, some studies attempted to associate Lp(a) with incident ASCVD by coagulation Factor VIII level while controlling for high-sensitivity C-reactive protein (hs-CRP). Researchers analyzed data from 6495 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA). Over a median follow-up of 13.9 years, 247 ischemic stroke events occurred. Lp(a) exhibited no correlation with ischemic stroke, irrespective of Factor VIII or hs-CRP levels. ²⁴

Regarding the contribution of Lp(a) to atrial fibrillation (AF), the most frequent risk factor of cardioembolic strokes, ²⁵ a study analyzed 20,432 incident AF cases from the UK Biobank (N = 435,579) using measured and genetically predicted Lp(a) levels. Mendelian randomization analyses using independent data were conducted. An increase of 50 nmol/L in the Lp(a) level was linked to an increased risk of incident AF, demonstrated for both measured (HR: 1.03) and genetically predicted Lp(a) (OR: 1.03). This effect was confirmed in Mendelian randomization analyses [OR: 1.04 per 50 nmol/L increase in Lp(a)]. A mere 39% of the risk associated with Lp(a) was conveyed through ASCVD, indicating that Lp(a) exerts an influence on AF that is, to some extent, independent of its effects on ASCVD. ²⁶

The influence and contribution of genetically proxied PCSK9 inhibition to ischemic stroke risk reduction was assessed using data from 310,020 individuals from the UK Biobank via identification of 10 PCSK9 gene variants linked to low PCSK9 and low-density lipoprotein cholesterol (LDL-C) levels, which were used as proxies for PCSK9 inhibition. Mendelian randomization analyses were conducted to explore the effects of genetically proxied PCSK9 inhibition on Lp(a) levels and ischemic stroke risk (60,341 cases, 454,450 controls). PCSK9 inhibition was associated with a 4% decrease in the log-Lp(a) level for each standard deviation decrease in the PCSK9 level. An estimated 0.5% reduction in the risk for atherosclerotic ischemic stroke risk was found, while the decrease in Lp(a) levels accounted for a mere 3.2% of the overall reduction in ischemic stroke risk. ²⁷

Compared with placebo, alirocumab administration effectively reduced the risk of any stroke and ischemic stroke, without elevating the risk for hemorrhagic stroke, in 18,924 patients from the ODYSSEY OUTCOMES study [any stroke: HR 0.72 (95% CI 0.57 − 0.91); ischemic stroke: HR 0.73 (95% CI 0.57 − 0.93); hemorrhagic stroke: HR 0.83 (95% CI 0.42 − 1.65)]. However, median baseline Lp(a) levels were similar in patients with and without a history of cerebrovascular disease (22.4 mg/dL [95% CI 7.6 − 62.1] and 21.2 mg/dL [95% CI 6.9 − 57.5), respectively; p = 0.09]. ²⁸ In the FOURIER trial, evolocumab treatment demonstrated a significant reduction in the risk of ischemic stroke [HR 0.75 (95% CI 0.62–0.92)], while showing no significant effect on hemorrhagic stroke (HR 1.16 [95% CI 0.68–1.98]). Notably, the FOURIER trial revealed that attaining a marked decrease in LDL-C levels did not elevate the risk of hemorrhagic stroke. ²⁹ It is important to emphasize that in the FOURIER trial, evolocumab achieved a median Lp(a) level reduction of 26.9%. However, in the ODYSSEY OUTCOMES trial, alirocumab demonstrated a median Lp(a) reduction of 5 mg/dL, with each 5 mg/dL decrease in Lp(a) correlating with a 2.5% reduction in CVD risk. ⁵ However, while PCSK9 inhibition reduces stroke risk, this may not solely relate to Lp(a) reduction, with concurrent LDL-C reduction likely playing a role; this effect should be studied in future large trials.

Two case reports deliberately describe the genetic aspect of high Lp(a) in cerebrovascular events. In a case report of a 46-year-old female patient with an Lp(a) level of 210 mg/dL who suffered an ischemic stroke, genetic analysis identified a new compound heterozygous deletion within the LPA gene. The study suggested that the genetic LPA variants of the patient were likely correlated with the increased Lp(a) level and the occurrence of ischemic stroke. ³⁰ Elevated Lp(a) levels may also influence the phenotype of inherited cerebral vasculopathies, as observed in a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with an elevated Lp(a) level of 142 mg/dL. The patient’s history comprised recurrent TIAs and a later ischemic stroke. Family members with CADASIL also exhibited elevated Lp(a) levels. Clinical findings in the index patient revealed steno-occlusive arteriopathy in large intracranial vessels and artery-to-artery embolic stroke. This is an atypical phenotype of CADASIL, possibly caused by the influence of Lp(a), and thus the authors advocated performing Lp(a) measurement in CADASIL patients with intracranial arterial stenoses, emphasizing its impact on the cerebrovascular phenotype. ³¹

Lp(a) and stroke recurrence

A prospective study followed up 250 patients with acute ischemic stroke (AIS) from the prospective Berlin Cream & Sugar study, conducted between January 2009 and August 2014, for 12 months. After accounting for potential confounding factors, patients with elevated Lp(a) levels had a notably higher risk of recurrent events, with an HR of 2.60 (95% CI 1.19–5.67; p = 0.016). ³²

In another prospective cohort study from the Third China National Stroke Registry involving 9899 patients with ischemic stroke risk or TIA who had plasma Lp(a) measurements and were followed up for 1 year, the risk of stroke recurrence was found to be higher in patients with Lp(a) levels > 50 mg/dL than in those with Lp(a) levels < 50 mg/dL (11.5% versus 9.4%, respectively). In this study, LDL-C was also corrected for Lp(a)-derived cholesterol (LDL-Cc). In patients with elevated Lp(a) levels and low LDL-Cc (<55 mg/dL) or low inflammatory markers [interleukin 6 (IL-6) < 2.65 ng/L], the increased stroke risk associated with elevated Lp(a) was less pronounced. There was no observed interaction between LDL-Cc, IL-6, or hs-CRP and Lp(a) levels in terms of stroke recurrence risk. ³³

Dyslipidemia, especially an elevated LDL-C level, is a risk factor for CVD. Statin therapy is the cornerstone and first choice in treating hypercholesterolemia; however, statins may actually increase plasma Lp(a) levels.^5,6 A prospective cohort study investigated the factors associated with alterations in Lp(a) levels and examined the connection between Lp(a) and recurrent vascular events in 303 patients on statin therapy with a first AIS over the course of 26 months. Statin treatment increased the Lp(a) level in 50.5% of patients, with a mean percent change in the Lp(a) level of 14.48% (95% CI 6.35–22.61). High on-statin Lp(a) levels (≥70 mg/dL) and changes in Lp(a) levels were associated with the risk of recurring vascular events in patients treated with statins for their first AIS. In addition, having a high on-statin Lp(a) level (≥70 mg/dL) increased the risk of recurrent vascular events in patients with LDL-C levels less than 1.8 mmol/L (70 mg/dL). ³⁴

In the setting of secondary prevention, aspirin is currently used in everyday clinical practice to prevent recurrent events because it has been proven to achieve a 25% reduction in major adverse cardiovascular events (MACEs), including stroke events. For potential future first-time events, aspirin is not recommended in adults older than 60 years, and its use should be a decision tailored to each patient in adults aged 40 to 59 years with very high risk of CVD, as outlined by the updated 2021–2022 USPSTF guidelines, because of the potential risk of bleeding. Regarding primary prevention in patients with hyperlipoproteinemia (a), in the Women’s Health Study, aspirin administration produced a twofold reduction in MACEs in LPA single-nucleotide polymorphism rs3789220 carriers. In addition, in the ASPREE trial, aspirin reduced MACEs by 11.4 and 3.3 events per 1000 person-years in LPA single-nucleotide polymorphism rs3789220 carriers and in participants with 43 elevated Lp(a)-related variants, respectively. ³⁵ Thus, future ischemic/atherothrombotic strokes linked to certain LPA variants may be prevented with aspirin administration. However, the balance between its benefits and risks warrants further evaluation, and a universal recommendation for its use regarding primary prevention cannot be made at this time.

Lp(a) and post-ischemic stroke outcomes

A prospective study examined 973 patients with available baseline plasma Lp(a) levels and set the primary outcome as death or major disability (modified Rankin scale score of 3–6) at 6 months. The primary outcome occurred in 20.7% of patients at 6 months. Elevated Lp(a) levels were associated with an increased risk of major disability or death at 6 months in patients with AIS, even when LDL-C was controlled. Furthermore, patients with high Lp(a) and low LDL-C levels had a higher risk of unfavorable functional outcomes (adjusted OR: 1.59, 95% CI: 1.01–2.52) than those with concordant levels. ³⁶ A study assessed 1017 patients diagnosed with AIS or TIA from the cognition subgroup of the Third China National Stroke Registry, which examined the association between Lp(a) levels and cognitive impairment after stroke using the Montreal Cognitive Assessment. In total, 326 participants (32.1%) presented with impaired cognition at 1 year. Increased serum Lp(a) levels were associated with cognitive impairment and reduced cognitive improvement following AIS or TIA in cases with the large artery atherosclerosis subtype [highest Lp(a) quartile, adjusted OR: 2.63; 95% CI: 1.05–6.61, p < 0.05]. This association was not observed in the small artery occlusion subtype. ³⁷

Racial disparities in the relationship between elevated Lp(a) levels and stroke risk, particularly among African Americans are evident, necessitating further large-scale trials to elucidate the associated genetic or environmental factors. Mendelian randomization analyses confirm a partial causal link between genetically elevated Lp(a) levels and ischemic stroke, underlining the genetic impact on stroke susceptibility. Additional studies explored and indicated an indirect association of Lp(a)-related stroke events with factors such as fibrinogen, AF, and PCSK9 regulation. Further evidence for the link between genetically elevated Lp(a) and cerebrovascular incidents is presented in the two case reports mentioned earlier in this section. Finally, heightened Lp(a) levels are linked to increased stroke recurrence; however, this risk may decrease with low LDL-C levels and inflammation markers. Elevated Lp(a) levels are notably associated with adverse post-ischemic stroke outcomes, including cognitive impairment, disability, and death.

A summary of the results of the clinical studies—in order of reference—pertaining to the effects of Lp(a) on cerebrovascular disease in adults is shown in Table 1.

Table 1.

Lipoprotein(a) and cerebrovascular disease in adults.

Name	Study Design	Purpose/Intervention	Results
12 Emerging Risk Factors Collaboration	Meta-analysis with 36 eligible prospective studies from January 1970 to March 2009, involving 126,634 participants in total	Association between Lp(a) concentration and significant vascular and non-vascular outcomes	Adjusted RR for ischemic stroke: 1.10 (95% CI 1.02–1.18) per 3.5-fold increase in Lp(a) level
13 Kumar et al.	Meta-analysis including41 eligible studies with 7874 ischemic stroke patients and 32,138 controls (13 studies of ischemic stroke subtypes) and 7 studies with 871 intracerebral hemorrhage patients and 2865 control subjects	Association between Lp(a) concentrations and the risk of stroke and its subtypes	Increased Lp(a) levels significantly associated with:Ischemic stroke (SMD 0.76; 95% confidence interval 0.53–0.99)Large artery atherosclerosis subtype of ischemic stroke (SMD 0.68; 95% CI 0.01–1.34)Intracerebral hemorrhage (SMD 0.65; 95% CI 0.13–1.17)
17 Smolders et al.	Meta-analysis with 31 eligible studies involving 56,010 subjects with over 4609 stroke events, as follows:23 case–control studies, 2600 strokes3 nested case–control studies, 364 strokes5 prospective cohorts with over 1645 strokes	Association between Lp(a) concentrations and the risk of stroke	Case–control studies: increased Lp(a) levels in stroke cases (SMD 0.39; 95% CI 0.23–0.54); Lp(a) more frequently abnormally elevated (OR, 2.39; 95% CI 1.57–3.63)Nested case–control studies: Lp(a) not a risk factor for incident stroke (OR, 1.04; 95% CI 0.6–1.8)Cohort studies: incident stroke more frequent in the highest tertile of Lp(a) distribution than in the lowest tertile (RR, 1.22; 95% CI 1.04–1.43)
18 Nave et al.	Meta-analysis with 20 eligible studies, involving 90,904 subjects and 5029 stroke events, as follows:11 case–control studies9 prospective studies	Association between Lp(a) concentrations and the risk of stroke; potential subgroup risk differences	Comparison of high with low Lp(a) levelsCase control studies: OR 1.41 (95% CI 1.26–1.57)Prospective studies: RR 1.29 (95% CI 1.06–1.58)Subjects younger than 55 years old had an increased RR of stroke compared with older participants
19 Ohira et al.; ARIC study	Cohort study with 14,221 participants (3647 Black and 10,574 White participants) from the ARIC study, aged 45 to 64 years and free of clinical cardiovascular disease, followed up for 13.5 years	Association between Lp(a) levels and the incidence of ischemic stroke among African Americans and Caucasians	496 ischemic strokes in the course of 13.5 yearsLp(a) > 300 μg/mL (30 mg/dL) compared with <100 μg/mL (10 mg/dL):79% higher age-, sex-, and race-adjusted RR of ischemic strokeMulti-variate adjusted RRs: 1.84 (95% CI 1.05–3.07) in Black women, 1.72 (95% CI 0.86–3.48) in Black men, 2.42 (95% CI 1.30–4.53) in White women, and 1.18 (95% CI 0.47–2.90) in White men
20 REGARDS study	Multicenter study including 30,239 Black and White US adults aged 45 and older, recruited between 2003 and 2007	Association between Lp(a) levels and the incidence of ischemic stroke among races	Fourth Lp(a) quartile: weak association with overall ischemic stroke, HR 1.45 (95% CI 0.96–2.19)Stronger association between Lp(a) and ischemic stroke in Black participants (HR 1.96, 95% CI 1.10–3.46) than in White participants (HR 1.14, 95% CI 0.64–2.04)
21 Huang et al.	Mendelian randomization study with data from two large genome-wide association study databases	Association between Lp(a) levels and stroke	Marginal causal relationship between genetically predicted Lp(a) and total stroke [OR (95% CI): 1.003 (1.001–1.006), p = 0.010]; ischemic stroke [OR (95% CI): 1.004 (1.001–1.007), p = 0.004], and large artery atherosclerotic stroke [OR (95% CI): 1.012 (1.004–1.019), p = 0.002]
22 Wang et al.	Mendelian randomization study based on various large genome-wide association study databases for Lp(a) levels and CVD, including ischemic stroke and subtypes	Association between Lp(a) levels and CVD	Causal relationship between elevated Lp(a) levels and large artery atherosclerotic stroke (OR = 1.003, 95% CI 1.002–1.004), not observed with total stroke and other stroke subtypes
23 Youyou et al.	Case–control study, involving 516 patients with ischemic stroke, matched 1:1 with individuals without ischemic stroke based on age and sex	Mediating role of fibrinogen in the association between Lp(a) levels and ischemic stroke	Significantly higher Lp(a) levels in subjects with ischemic stroke (p < 0.001)27% higher odds of ischemic stroke occurrence with each standard deviation increase in Lp(a) levelsFibrinogen accounted for 10.15% of the association between Lp(a) and the risk of ischemic stroke
24 Colantonio et al.	Data from 6495 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA)	Association of Lp(a) with incident ASCVD by levels of coagulation Factor VIII while controlling for hs-CRP	247 ischemic strokes occurred over the course of 13.9 yearsNo correlation of Lp(a) with ischemic stroke, irrespective of Factor VIII or hs-CRP levels
26 Mohammadi-Shemirani et al.	Observational study with 20,432 incident AF cases from the UK Biobank (N = 435,579), using measured and genetically predicted Lp(a) levelsMendelian randomization analysis with data for AF from publicly available genome-wide association studies (N = 1,145,375)	Role of Lp(a) in AF and investigation of association with ASCVD	A 50-nmol/L increase in the Lp(a) level was linked to an increased risk of incident AF, demonstrated for both measured (HR: 1.03) and genetically predicted Lp(a) (OR: 1.03), also confirmed in the separate Mendelian randomization analysis39% of the risk associated with Lp(a) was conveyed through ASCVD
27 De Marchis et al.	Mendelian randomization analysis of ischemic stroke (60,341 cases, 454,450 controls)	Effects of genetically proxied PCSK9 inhibition on Lp(a) levels and ischemic stroke	PCSK9 inhibition was associated with a 4% decrease in logarithmic Lp(a) levels per one standard deviation decrease in PCSK9 level0.5% reduction in the odds for atherosclerotic ischemic strokeDecrease in Lp(a) level responsible for 3.2% of the overall risk reduction in ischemic stroke
28 Jukema et al.	Prespecified analysis based on 18,924 patients from the ODYSSEY OUTCOMES study	Effective reduction of any stroke and ischemic stroke risk with alirocumab administration versus placebo for 1 to 12 months	Alirocumab administration effectively reduced the risk of any stroke and ischemic stroke without elevating the risk for hemorrhagic stroke [any stroke: HR 0.72 (95% CI 0.57–0.91); ischemic stroke: HR 0.73 (95% CI 0.57–0.93); hemorrhagic stroke: HR 0.83 (95% CI 0.42–1.65)]Similar median baseline Lp(a) levels in patients with and without a history of cerebrovascular disease
29 Giugliano et al; the FOURIER trial	Prespecified analysis of cerebrovascular events in the overall population of the FOURIER trial	Association of evolocumab administration versus placebo with reduction of stroke occurrence	Evolocumab demonstrated a significant reduction in the risk of ischemic stroke [HR 0.75 (95% CI 0.62–0.92)], with no significant effect on hemorrhagic stroke [HR 1.16 (95% CI 0.68–1.98)]Evolocumab achieved a median Lp(a) level reduction of 26.9%
32 Lange et al.	Prospective cohort study involving 250 patients with acute ischemic stroke from the prospective Berlin Cream & Sugar study, followed up for 12 months	Risk for recurrent cardiovascular and cerebrovascular events in patients with first ischemic stroke incident with elevated Lp(a)	Patients with elevated Lp(a) levels had a notably higher risk of recurrent events, with an HR of 2.60 (95% CI 1.19–5.67; p = 0.016)
33 Xu et al.	Prospective cohort study involving 9899 patients with ischemic stroke or TIA from the Third China National Stroke Registry, followed for 1 year	Association between Lp(a) and the risk of recurrent stroke in general and on the basis of low LDL-C and inflammatory levels	Risk of stroke recurrence higher in patients with Lp(a) levels > 50 μg/mL than in those with Lp(a) levels < 50 μg/mL (11.5% versus 9.4%)Elevated Lp(a) levels and low LDL-Cc or low IL-6 levels: stroke risk associated with elevated Lp(a) less pronouncedNo observed interaction between LDL-Cc, IL-6, or hs-CRP and Lp(a) levels in terms of stroke recurrence risk
34 Wang et al.	Prospective cohort study involving 303 patients with a first acute ischemic stroke and on statin therapy, followed up for 26 months	Factors linked with alterations in Lp(a) levelsConnection between Lp(a) and recurrent vascular events	Statin treatment increased the Lp(a) level in 50.5% of patients, with a mean percent change in the Lp(a) level of 14.48%High on-statin Lp(a) levels (≥ 70 mg/dL) and changes in Lp(a) levels were associated with the risk of recurring vascular events in patients treated with statins for their first acute ischemic strokeHigh on-statin Lp(a) levels (≥ 70 mg/dL) increased the risk of recurrent vascular events in patients with LDL-C levels less than 1.8 mmol/L
36 Dong et al.	Prospective cohort study involving 973 patients with baseline Lp(a) levels	Association between Lp(a) and unfavorable functional outcome among patients with acute ischemic stroke with discordant Lp(a) and LDL-C levels	Primary outcome: 20.7% of patients died or experienced major disability at 6 monthsHigh Lp(a) and low LDL-C levels: higher risk of unfavorable functional outcomes (adjusted OR: 1.59, 95% CI: 1.01–2.52) compared with concordant levels
37 Li et al.	Prospective study involving 1017 patients with ischemic stroke or TIA from the cognition subgroup of the Third China National Stroke Registry, followed for 1 year	Association between Lp(a) levels and cognitive impairment after stroke	326 participants (32.1%) with impaired cognition at 1 yearIn patients with the large artery atherosclerosis subtype: higher serum Lp(a) levels were associated with cognitive impairment and reduced cognitive improvement following ischemic stroke or TIA (adjusted OR: 2.63; 95% CI: 1.05–6.61, p < 0.05)

Lp(a), lipoprotein (a); CI, confidence interval; OR, odds ratio SMD, standardized mean difference; RR, risk ratio; HR, hazard ratio; CVD, cardiovascular disease; ASCVD, atherosclerotic cardiovascular disease; hs-CRP, high-sensitivity C-reactive protein; AF, atrial fibrillation; TIA, transient ischemic attack; LDL-C, low-density lipoprotein cholesterol; LDL-Cc, lipoprotein (a)-derived cholesterol IL-6, interleukin-6.

Lp(a) and cerebrovascular events in pediatric patients

The role of Lp(a) in children and youth is an intriguing topic. Lp(a) is detectable in newborn infants, with gestational age influencing levels. Umbilical cord blood Lp(a) exhibits a robust correlation with measurements in neonatal venous blood, and this correlation persists at both 2 and 15 months of age. Elevated Lp(a) levels at birth, especially those surpassing the 90th percentile (> 42 mg/dL), predict elevated levels at 15 months. The expression pattern of Lp(a) in childhood is distinctive, maintaining a consistent trajectory into adulthood, and is strongly influenced by genetic inheritance. Childhood Lp(a) variability exists, with some studies indicating an increased level in adulthood. However, the clinical impact of childhood Lp(a) fluctuations may not be significant. ³⁸

Evidence from the pediatric population indicates that Lp(a) increases the likelihood of future ASCVD. In the Young Finns Study, elevated Lp(a) levels (≥ 30 mg/dL) in youth were linked to an approximately twofold increased risk of developing adult ASCVD. In the Bogalusa Heart Study, white individuals aged 8 to 17 years old with a high Lp(a) level had a 2.5-times greater risk of adult ASCVD in an adjusted model, and this risk remained consistent when accounting for LDL-C and body mass index. ³⁹ Familial hypercholesterolemia (FH) is a well-studied factor that contributes to early atherosclerosis and ASCVD. In cases where children exhibit clinical symptoms of FH without a detected FH mutation, elevated serum Lp(a) levels emerge as a potential culprit, especially when compared with a definitive FH diagnosis. This occurs possibly because Lp(a) levels are included in the measurement of LDL-C. These findings underscore the importance of measuring Lp(a) levels in children when FH is suspected. ⁴⁰ The Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents advises against routine screening of the Lp(a) level because of the lack of adequate relevant clinical trials. However, they suggest considering Lp(a) measurement in youth with a history of ischemic or hemorrhagic stroke or those with a parental history of ASCVD not explained by classical risk factors. ⁴¹ However, recent data from a pediatric lipid clinic indicate that Lp(a) measurements should be conducted at least twice during childhood and, if the patient only had Lp(a) assessed during childhood, the measurement should be repeated in adulthood. ⁴² Some authors recommend that routine Lp(a) screening should be offered to pre-adolescents and young adults, as this would determine those at high risk for ASCVD with the intent of early intervention, if required. ⁴³ According to a special scientific statement by the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young, Lp(a) level screening is not warranted, although elevated Lp(a) is recognized as a risk factor for hypercoagulability. ⁴⁴ Nevertheless, in youth found to have elevated Lp(a) levels, it is important to emphasize early and lifelong adoption of a heart-healthy lifestyle, especially with respect to smoking avoidance or cessation, given the thrombotic risk attributable to Lp(a). ⁴⁵

Lp(a) serves as a contributing factor to arterial AIS, including recurrences. In a selection of 14 observational studies involving children with AIS and available data on the lipid profile, Lp(a) was positively associated with AIS, with a pooled OR of 4.24. ⁴⁶ A case–control study that matched 52 children with imaging-confirmed AIS with 78 age- and sex-matched healthy controls showed that the median Lp(a) level was higher in the AIS group than that in the control group [11.85 (range: 1.90–140) mg/dL versus 6.02 (range: 0.64–76.8) mg/dL, respectively; p < 0.05). In 26.9% of the patients in the AIS group, the Lp(a) level was > 30 mg/dL, and serum levels exceeding 50 and 100 mg/dL were also observed more commonly in the AIS group. In fact, a patient with an Lp(a) level surpassing 66 mg/dL experienced three recurrent events, confirming a positive correlation between increased serum Lp(a) levels and ischemic stroke recurrence. ⁴⁷ In another case–control study conducted with predominantly White US children, a noteworthy correlation emerged. An elevated Lp(a) level beyond the 90th percentile, using race-specific cutoffs, exhibited a substantial impact on recurrent AIS, as evidenced by a robust OR of 14.0 (CI 1.0–184, p = 0.05). Notably, this observed impact was correlated with a smaller apo(a) isoform size, as an isoform size below the 10th percentile was associated with AIS recurrence [OR: 12.8 (CI 1.61–101), p = 0.02]. The authors recommended Lp(a) measurement for pediatric patients with a history of AIS in the setting of secondary prevention. ⁴⁸

A systematic review evaluated 22 studies enrolling 1764 patients (neonate to 18 years of age) with AIS or cerebral venous sinus thrombosis and 2799 controls. A statistically significant correlation between elevated serum Lp(a) levels and first stroke occurrence in children was observed (OR 6.27; 95% CI 4.52–8.69), ⁴⁹ with Lp(a) exhibiting fibrinogen-like properties and acting as a prothrombotic factor, a pathophysiological mechanism also suggested by Goldenberg et al. ⁴⁸ A serum Lp(a) level exceeding 30 mg/dL has been implicated in cerebral venous thrombosis, both as an independent risk factor (OR 7.2%, 95% CI 3.7–14.2) and in combination with prothrombotic risk factors, such as the Factor V G1691A mutation, Factor II G20210A, antithrombin type I deficiency, protein C type I deficiency, and anticardiolipin antibodies (multivariate analysis OR 4.1, 95% CI 2.0–8.7). ⁵⁰ Overall, elevated Lp(a) in children and youth not only increases the risk of incident thrombosis and ischemic stroke by approximately four times, ⁵¹ but also enhances their susceptibility to recurrent events.

In the context of a positive family history, Lp(a) is identified as a factor that may influence homocysteine levels. In particular, a study explored the correlation between Lp(a) and the homocysteine level, an established prothrombotic factor, in stroke patients and their children, with an average age of 17.5 years. Homocysteine and Lp(a) concentrations increased in tandem with the severity of ischemia, peaking in patients experiencing a complete stroke (averages of 15.1 µmol/L and 32.9 mg/dL, respectively). This pattern was mirrored in their offspring, where the most elevated values were found in children of those with complete stroke occurrences (12.6 µmol/L and 23.0 mg/dL, respectively). The control values of homocysteine and Lp(a) were significantly lower (8.7 µmol/L and 5.35 mg/dL, respectively). A nearly linear correlation of Lp(a) levels (r = 0.87, p < 0.0001) existed between parents and children, with a modest correlation between Lp(a) and homocysteine in children (r = 0.47, p < 0.05). ⁵²

Occurring in 1 to 13 cases per 100,000 children, AISs demonstrate a frequency roughly seven times less than that in adults. In addition, approximately 40% of cases are diagnosed as cryptogenic. ⁵³ Nonetheless, case reports regarding strokes in children are scarce, yet noteworthy. Two distinct case reports describe two 11-year-old boys exhibiting neurological symptoms consistent with posterior circulation infarcts, linked to steno-occlusive arteriopathy and thrombi. In both cases, an elevated Lp(a) level was the sole identifiable risk factor, measuring 131 mg/dL in the first instance and 269 nmol/L (107.6 mg/dL) in the second. Apart from implementing secondary stroke prevention protocols, management included lipoprotein apheresis in the first case and administration of nicotinic acid in the second to reduce Lp(a).^53,54

Data concerning stroke during the perinatal and neonatal period are intriguing. A French cohort study supported the hypothesis that an elevated maternal Lp(a) level increases the risk of neonatal AIS. In this multicenter study of children with AIS, 65 mother and child pairs underwent a complete set of studies. Among them, 45 (69%) pairs had concordant Lp(a) values, and in 30 of 65 pairs (46%), the Lp(a) value was elevated in the mother, child, or both. An elevated Lp(a) level (> 30 mg/dL) was observed in 26 mothers (38%) and in 15 children (22%); both rates were higher than the reference range reported in the general Caucasian population (10% in adults and 5% in children). In addition, a strong positive correlation between maternal and offspring Lp(a) levels (p < 0.0001) was observed, along with a positive correlation between high maternal Lp(a) levels and low birth weight (p = 0.027). These data suggest that the demonstrated increased risk of AIS in children with elevated maternal Lp(a) may be mediated through impaired vascular placental function. ⁵⁵ In another study involving 60 mother-child pairs, a statistically significant difference (p < 0.0001) was observed between the general population and mothers of children with perinatal arterial stroke with regard to elevated serum Lp(a) levels, among other prothrombotic factors. In addition, in this study, 33% of mothers and 21% of children with perinatal AIS presented elevated Lp(a) levels. ⁵⁶

In a study that examined outcomes of therapy and quality of life in 20 boys with past cerebrovascular events for a median follow-up time of 3.7 years, the Lp(a) level was elevated in 55% of the sample (11 of 20 children), including all 5 with hemorrhagic stroke and 6 of 15 (40%) with ischemic stroke. Thus, an elevated Lp(a) level constituted the predominant risk factor in pediatric patients with stroke. Quality of life and overall outcomes were determined by the severity of neurological deficits. ⁵⁷

A summary of the results of the clinical studies—in order of reference—pertaining to the effects of Lp(a) on cerebrovascular disease in pediatric patients is shown in Table 2.

Table 2.

Lipoprotein(a) and cerebrovascular disease in pediatric patients

Name	Study design	Purpose/Intervention	Results
40 de Boer et al.	Cross-sectional study involving 2721 children with a mean age of 10.3 years, with and without FH, and with Lp(a) measurements available	Association of Lp(a) levels with a clinical presentation of FH in children	32% of children with probable FH were found to have high Lp(a)Lp(a) was significantly higher and more frequently elevated in children with probable FH than in children with definite FH and unaffected siblings
42 de Boer et al.	Large cohort study involving 2740 children referred to a pediatric lipid clinic from 1989 to 2017	Evaluation of Lp(a) level alterations related to age and intra-individual variation of Lp(a) levels	From the age of 8 years onwards, mean Lp(a) increased by 22% in children who reached adulthood without lipid-lowering medicationIn statin-users and children who used ezetimibe additionally, Lp(a) increased by 43% and 9%, respectivelyThe intra-individual variation of Lp(a) was 70%
46 Sultan et al.	Systematic review of 14 observational studies	Association of Lp(a) levels with arterial ischemic stroke in children	Elevated Lp(a) levels and ischemic stroke were positively associated with a pooled OR of 4.24
47 Teber et al.	Case–control study involving 52 children with imaging-confirmed arterial ischemic stroke, matched with 78 age- and sex-matched healthy controls	Association of Lp(a) levels with childhood arterial ischemic stroke	Higher median Lp(a) levels in the arterial ischemic stroke group than in the control group [11.85 (range: 1.90–140) mg/dL versus 6.02 (range:0.64–76.8) mg/dL; p < 0.05)26.9% of patients in the case group had Lp(a) > 30 mg/dL
48 Goldenberg et al.	Case–control study with 43 patients having experienced a childhood arterial ischemic stroke and 127 healthy controls	Association of Lp(a) levels and apo(a) isoform size with arterial ischemic stroke in children	Lp(a) level above the 90th percentile strongly associated with arterial ischemic stroke (OR 14.0)Smaller apo(a) isoform size, below the 10th percentile, also associated with arterial ischemic stroke (OR 12.8, 95% CI 1.61–101, p = 0.02)
49 Kenet et al.	Meta-analysis involving 22 studies with 1764 patients (neonate to 18 years of age) with arterial ischemic stroke or cerebral venous sinus thrombosis and 2799 controls	Impact of thrombophilia on first ischemic stroke in children	Statistically significant correlation between elevated serum Lp(a) levels and first stroke occurrence in children (OR 6.27; 95% CI 4.52–8.69)
50 Heller et al.	Case–control study involving 149 pediatric patients (cases) with CVT and 149 children with similar clinical conditions but without CVT (controls)	Association of prothrombotic factors with childhood CVT	Lp(a) levels > 30 mg/dL were implicated in CVT, both as an independent risk factor (OR 7.2%, 95% CI 3.7–14.2) and in combination with prothrombotic risk factors, such as the Factor V G1691A mutation, Factor II G20210A, antithrombin type I deficiency, protein C type I deficiency, and anticardiolipin antibodies (multivariate analysis OR 4.1, 95% CI 2.0–8.7)
52 Torbus-Lisiecka et al.	Study involving 35 patients with early stroke and their children (mean age 17.5 years)	Association between homocysteine levels and severity of ischemic strokeCorrelation of Lp(a) levels and homocysteine levels	Homocysteine and Lp(a) concentrations increased in tandem with the severity of ischemia, peaking in patients experiencing a complete stroke (15.1 µmol/L and 32.9 mg/dL, respectively)Pattern mirrored in offspring, with peak values in those from parents with complete strokes (12.6 µmol/L and 23.0 mg/dL, respectively)Significantly lower levels in controlsNearly linear correlation of Lp(a) levels (r = 0.87, p < 0.0001) existed between parents and children; modest correlation between Lp(a) and homocysteine in children (r = 0.47, p < 0.05)
55 Renaud et al.	Prospective cohort study of children with arterial ischemic stroke involving 65 mother and child pairs	Role of Lp(a) in neonates with stroke	Lp(a) level > 30 mg/dL was observed in 26 mothers (38%) and in 15 children (22%); higher rates than the reference populationStrong positive correlation between maternal and offspring Lp(a) levels (p < 0.0001)Positive correlation between high maternal Lp(a) levels and low birth weight (p = 0.027)
56 Curry et al.	Study of 60 mother and child pairs with perinatal ischemic stroke	Demographic, historical, and prothrombotic risk factors in infants with perinatal arterial stroke and their mothers	Statistically significant difference (p < 0.0001) in elevated serum Lp(a) levels between the general population and mothers of children with perinatal arterial strokeElevated Lp(a) levels in 33% of mothers and 21% of children with perinatal ischemic stroke
57 Simma et al.	Retrospective population-based study of 20 boys with past cerebrovascular events, median follow-up time of 3.7 years	Pediatric stroke occurrence, relevant risk factors, outcomes of therapy and quality of life	Elevated Lp(a) levels in 55% of the sample (11 of 20 children), including all 5 with hemorrhagic stroke and 6 of 15 (40%) with ischemic strokeRisk factors: vasculopathy (85%), lipometabolic disorders (85%), and prothrombotic abnormality (50%)Quality of life and overall outcomes determined by the severity of neurological deficits

Lp(a), lipoprotein (a); FH, familial hypercholesterolemia; OR, odds ratio; apo(a), apolipoprotein (a); CI, confidence interval; CVT, cerebral venous thrombosis; ARIC, Atherosclerosis Risk in Communities.

Conclusions and future directions

As described above, Lp(a) is an atherogenic lipoprotein, and its level is largely genetically predetermined. When elevated, serum Lp(a) levels prompt the development of ASCVD. Stroke, in particular, affects a significant part of the entire global population. Its burden is constantly increasing, impacting not only quality of life but also, secondarily, the global economy. This makes stroke a major contemporary health hazard and a significant challenge not only for neurologists, but for the medical community in general. Ample evidence from systematic reviews, meta-analyses, prospective and retrospective studies, and case reports demonstrates a strong positive correlation between elevated serum Lp(a) levels and stroke occurrence, especially of the ischemic type. Furthermore, elevated Lp(a) levels favor recurrence of cerebrovascular accidents. Measurement of Lp(a) in adults is recommended at least once in their lifetime, and additional measurements are indicated if there is a history of ischemic stroke, premature ASCVD, or extremely elevated serum Lp(a) levels. In children, Lp(a) is of major importance in the pathogenesis of ischemic stroke, especially in the absence of other prothrombotic factors. Therefore, Lp(a) measurement is warranted for pediatric patients with a history of stroke or a family history of ASCVD.

Given the correlation between Lp(a) and cerebrovascular events, it is reasonable to pursue reduced Lp(a) levels, which is not an effortless task. To date, currently approved lipid-lowering agents can only achieve modest reductions of Lp(a) levels. Lp(a) constitutes a risk factor for cerebrovascular accidents; however, the clinical challenge lies in the absence of solid available treatment options. In this regard, previously suggested agents such as niacin, aspirin, and PCSK9 inhibitors have already shown moderate success in managing hyperlipoproteinemia (a) and related vascular outcomes. Yet, clinicians find themselves with no approved treatment options in their arsenal. Until approved agents make their way into everyday clinical practice, lifestyle changes remain a cornerstone of treatment. Dietary modifications, such as supplementation with flaxseed and curcuminoids, have been shown by meta-analyses to modestly reduce Lp(a) levels.^58,59 In the case of obese patients with hypercholesterolemia (a), clinicians should be mindful that bariatric surgery has a moderate effect on reducing Lp(a) levels, as indicated by a meta-analysis of 13 studies. ⁶⁰ In cases of high Lp(a), it is crucial to aggressively manage modifiable risk factors such as LDL-C, blood pressure, diabetes, smoking, and excess weight, until it is ascertained whether treatment with pharmaceutical agents targeting Lp(a) confers any benefits in reducing the risk of stroke.

A summary of the results of the clinical studies—in order of reference—pertaining to the effects of dietary modifications and bariatric surgery on Lp(a) levels is shown in Table 3.

Table 3.

Effect of dietary modifications and bariatric surgery on Lp(a) levels

Name	Study design	Purpose/Intervention	Results
58 Sahebkar et al.	Meta-analysis of 6 randomized controlled trials	Impact of flaxseed supplementation on plasma Lp(a) levels	Significant reduction in plasma Lp(a) levels (SMD: −0.22, 95% CI: −0.41 to −0.04, p = 0.017)
59 Panahi et al.	Randomized controlled trial of 118 patients with type 2 diabetes mellitus	Efficacy of curcuminoids in improving serum lipids versus placebo in patients with type 2 diabetes	Significant reductions in serum levels of Lp(a) with curcuminoids versus placebo(−1.50 ± 1.61 versus −0.34 ± 1.73, respectively; p = 0.001)
60 Jamialahmadi et al.	Meta-analysis of 13 studies involving 1551 patients	Assessment of impact of bariatric surgery on Lp(a) levels	Significant reduction of Lp(a) levels following bariatric surgery(SMD: −0.438, 95% CI: −0.702, −0.174, p < 0.001, I 2: 94.05%)

Lp(a), lipoprotein (a); SMD, standardized mean difference; CI, confidence interval.

What does the future hold? With regard to novel agents targeting Lp(a) production, recent trials have demonstrated the potential for reductions exceeding 95%. HORIZON and OCEAN(a)–DOSE are two crucial phase-3 outcome clinical trials, each assessing the efficacy of pelacarsen and olpasiran, respectively, in reducing MACEs, including cerebrovascular accidents. Both trials are designed for large populations with elevated serum Lp(a) levels and established ASCVD. Their results are eagerly awaited, as they are expected to provide invaluable information regarding the optimal therapeutic management of hyperlipoproteinemia (a), which would also lead to the development of updated, evidence-based guidelines tailored toward the effective secondary prevention of ASCVD, including cerebrovascular accidents.^5,6,61

Promising short-interfering RNA agents aimed at preventing Lp(a) formation are currently undergoing testing. Examples include zerlasiran or SLN360 and lepodisiran, which inhibit the synthesis of apo(a), and muvalaplin, which blocks the apo(a)-apoB-100 interaction while avoiding interaction with plasminogen. Preliminary results from separate phase 1 trials demonstrate the efficacy of these agents with significant, predominantly dose-dependent, reductions observed for elevated Lp(a) levels while showing a favorable tolerability profile. Currently, phase 2 trials for the abovementioned agents are under development, with their results being eagerly awaited by the medical community. ⁶²

Genetic analysis of the LPA gene and precision medicine may aid in tailoring pharmacological management of Lp(a) in selected patients. ⁶³ Further randomized double-blinded outcome studies of specific Lp(a)-lowering therapies are needed to allow for more definitive conclusions and recommendations. These studies should exclusively examine the effects of novel RNA agents, inclisiran, and PCSK9 inhibitors on the epidemiology of ischemic or hemorrhagic strokes by reducing Lp(a). Standardization and re-evaluation of guidelines regarding Lp(a) measurement in pediatric patients should be considered, based on the evidence published in the literature, as presented earlier in this review.

ORCID iD

Constantine E. Kosmas https://orcid.org/0000-0003-3926-0304