See article vol. 33: 566-577
Accumulating evidence indicates that cirlcut lipoprotein (a) [Lp(a)] is an independent causal risk factor for atherosclerotic cardiovascular disease (ASCVD). For instance, numerous observational studies have consistently reported an association between elevated Lp(a) levels and subsequent ASCVD risk in both primary and secondary prevention settings. This collective evidence suggests that Lp(a) is a clinically applicable measure for stratifying the uncertainty risks of ASCVD.
Niwa et al. provided clinical evidence of how the integration of Lp(a) with the Suita score could improve the prediction of the presence of high-risk plaques 1) . They retrospectively analyzed 272 patients with suspected symptoms of coronary artery disease (CAD). Coronary plaques were evaluated using coronary computed tomography angiography (CTCA). Lp(a) levels were measured within four weeks prior to CTCA. A high-risk plaque (HRP) was defined as the presence of positive remodeling and/or low-attenuation plaques. The average age and Suita score of the study participants were 65 years old and 48 years old, respectively. Approximately 11% of the study participants received statins prior to CTCA. The median Lp(a) level were 38.6 nmol/L. On CTCA, 12.1% of the study subjects exhibited HRP. A multivariate logistic regression analysis revealed that both Suita score and Lp(a) level were independent predictors of HRP. Furthermore, elevated Suita scores and Lp(a) levels were associated with the severity of coronary atherosclerosis. Notably, the highest frequency of HRP was observed in those with both intermediate/high-risk Suita scores and Lp(a) ＞3rd tertile. The optimal cutoff value of Lp(a) levels to predict the presence of HRP was 60.0 nmol/L.
This analysis reaffirms an increasing body of clinical evidence demonstrating the association between Lp(a) and ASCVD. In particular, the association of Lp(a) with plaque measures on CTCA is consistent with the findings from other published studies using CTCA or intravascular imaging. One intriguing observation is that measurement of Lp(a) has the potential to identify patients with HRP even if their Suita scores are not at high risk levels ( average Suita score = 48). The Lp(a) level could be a clinically important measure to help physicians identify patients requiring CTCA.
Another important finding is that the cut-off value of Lp(a) levels (60.0 nmol/L) to predict HRP is lower than that in published studies. Most studies analyzing Caucasians have shown Lp(a) levels ＞125 nmol/L (50 mg/dL) as a risk factor associated with ASCVD. Given that Lp(a) levels in Asians are lower than those in Caucasians, these racial differences may account for the aforementioned observations. Table 1 summarizes the cutoff values in published studies, including Japanese patients 2 - 10) . In patients without ASCVD, an Lp(a) level ≥ 30 mg/dL was associated with an elevated risk of coronary heart disease 2) ( Table 1 ) . In patients with CAD, consistent associations between Lp(a) and ASCVD or plaque measurements were observed 3 - 7) ( Table 1 ) . In patients with heterozygous familial hypercholesterolemia, elevated risks of CAD and polyvascular disease were observed in those with high Lp(a) levels ( Table 1 ) . The cutoff values were between 15 and 50 mg/dL. Although definitions of high Lp(a) levels vary, a consistent association between elevated Lp(a) and increased cardiovascular risk has been observed in Japan, in line with international findings. Variability across studies was noted, likely due to differences in study design, endpoints, and follow-up duration 11) . Further evidence from a large-scale study population is required to establish a cutoff value of Lp(a) to predict ASCVD in Japanese patients.
Table 1. Recent publications about the Association of Lp(a) Levels with ASCVD in Japanese Patients (2021-2026).
| Author and journal | Study population | Statin | Lp(a) cut-off values | Findings |
|---|---|---|---|---|
| Patients without ASCVD | ||||
|
Arafa, et al. J Atheroscler Thromb. 2025;32:1139-1149.(2) |
participants without any history of CAD and stroke (n = 5138) |
7.2% (lipid-lowering agents) |
30 mg/dL | Lp(a) ≥ 30 mg/dL was associated with an increased risk of CHD in the Japanese population. |
| Patients with CAD | ||||
|
Shishikura, et al. J Clin Lipidol. 2025;19:509-520.(3) |
Patients with CAD (n = 439) |
66.9% | 50 mg/dL | A greater lipidic plaque content was observed at analyzed coronary lesions in patients with Lp(a) ≥ 50 mg/dL. |
|
Takahashi, et al. Am J Cardiol. 2022;168:11-16. (4) |
ACS patients receiving PCI (n = 1131) | 100% | 15 mg/dL | Patients with Lp(a) ≥ 15 mg/dL had a significantly higher risk of MACE (HR = 1.66, 95%CI = 1.05-2.61, p = 0.03). |
|
Tomoi, et al. JACC Cardiovasc Interv. 2022;15:1466-1476. (5) |
Patients with PAD receiving EVT (n = 1169) | 62.4% | 30 mg/dL |
The cumulative incidence rate of MACE (48.1% vs 27.3%) and MALE (67.9% vs 27.2%) was significantly higher in patients with high Lp(a) levels (p＜0.001 for both). The adjusted HR were 1.93 (95%CI = 1.44-2.59; p＜0.001) for MACE and 4.15 (95%CI 3 .14-5.50; p＜0.001) for MALE. |
|
Tada, et al. J Lipid Atheroscler. 2025;14:120-127. (6) |
Patients with Lp(a) measurement (n = 4512: 19.6% of them had CAD) |
25.9% (lipid-lowering agents) |
30 mg/dL | Lp(a) ≥ 30 mg/dL was associated with an elevated risk of CAD in patients with and without family history. |
|
Dai, et al. Circ J. 2023;87:1356- 1361. (7) |
AMI patients (n = 262) | 93.1% | 32 mg/dL | Lp(a) ≥ 32 mg/dL was an independent predictor of MACE (HR = 2.84, 95%CI = 1.25-6.60, p = 0.013). |
| Patients with HeFH | ||||
|
Funabashi, et al. J Am Heart Assoc. 2022;11:e025232. |
Clinical diagnosed HeFH (n = 370) | 87.3% | 50 mg/dL |
On multivariable analysis, Lp(a) ≥ 50 mg/dL (OR = 5.66, 95%CI = 1.68-19.0, p = 0.005) independently predicted polyvascular disease. |
|
Murai, et al. J Clin Lipidol. 2025;19:1273-1283. |
Clinical diagnosed HeFH (n = 484) | 88.0% | 30 mg/dL |
During a 15-year observational period, MACE occurred more frequently in patients with Lp(a) ≥ 30 mg/dL (log-rank p = 0.026). This Lp(a)-associated cardiovascular risk was further elevated among those with both cornes arcus and Achiles tendon thickness ≥ 14.0 mm (log-rank P = 0.042). |
|
Shishikura, et al. J Atheroscler Thromb. 2025;32:100-110. |
Clinical diagnosed HeFH (n = 147) | 82.3% | 28 mg/dL | Lp(a) level ≥ 28 mg/dL (p＜0.001) were independent predictors of CAD. |
ACS=acute coronay syndrome, AMI=acute myocardial infarction, CAD=coronay artey disease, CHD=coronary heart disease, CI=confidence interval, EVT=endovascular therapy, HeFH=heterozygous familial hypercholesterolemia, HR=hazrad ratio, Lp(a)=lipoprotein(a), MACE=major adverse cardiovacular disease, MALE=major adverse limb event, OR=odds ratio, PAD=peripheral artery disease
This study provides additional insights into the importance of integrating Lp(a) into clinical practice. The Suita score is an established risk stratification approach based on clinical characteristics. The combination of the Suita score and Lp(a) levels may further improve preventive management of future ASCVD. Since the current study included only symptomatic patients, whether risk stratification in asymptomatic patients is possible with the use of both the Suita score and Lp(a) levels remains to be determined. Preventive management according to the Suita score and Lp(a) levels may be effective in mitigating future risks of ASCVD. However, whether the addition of the Lp(a) measurement following the evaluation of the Suita score affects the commencement and selection of anti-atherosclerotic medical therapies has not yet been elucidated. Future studies are warranted to investigate the efficacy of these two measures-guided management on cardiovascular outcomes in Japanese patients.
Novel agents have recently been developed, and clinical trials are ongoing to investigate the efficacy of Lp(a)-lowering agents on cardiovascular outcomes in patients with elevated Lp(a) levels. Given that patients with both intermediate/high-risk Suita score and Lp(a) 60.0 nmol/L were more likely to exhibit HRP, these patients may be another therapeutic target requiring Lp(a)-lowering therapies. The development of Lp(a)-targeted therapies has the potential to improve cardiovascular outcomes since the emergence of statins. Ongoing clinical trials are expected to elucidate the effectiveness and safety of these novel agents. The population health impact can only be realized after these agents are delivered effectively to appropriate patients who are more likely to benefit from such agents. As a result, more work is needed to achieve these goals.
Conflicts of Interest
Yu Kataoka has received research support from Kowa, Nipro and Abbott.
References
- 1).Niwa Y, Naruse H, Kawai H, Sakaguchi E, Ishihara Y, Hattori H, Uehara K, Ito M, Yamada S, Yamada A, Muramatsu T, Kitagawa F, Takahashi H, Ishii J, Sarai M, Yanase M, Ozaki Y, Saito K, Izawa H. J. J Atheroscler Thromb, 2026; 33: 566-577 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2).Arafa A, Kato Y, Kokubo Y, Khairan P, Matsumoto C, M Nakao Y, Kataoka Y, Harada-Shiba M. Lipoprotein(a) Levels and the Risk of Coronary Heart Disease and Stroke: The Suita Study. J Atheroscler Thromb, 2025; 32: 1139-1149 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3).Shishikura D, Kataoka Y, Nicholls SJ, Ray KK, Puri R, Kusumoto H, Yamauchi Y, Sakane K, Fujisaka T, Morita H, Murai K, Iwai T, Sawada K, Matama H, Honda S, Fujino M, Yoneda S, Takagi K, Nakao K, Otsuka F, Nishihira K, Takamisawa I, Asaumi Y, Noguchi T, Harada-Shiba M, Hoshiga M. Characterization of lipidic plaque features in association with LDL-C＜70 mg/dL and lipoprotein(a) ＜50 mg/dL. J Clin Lipidol, 2025; 19: 509-520 [DOI] [PubMed] [Google Scholar]
- 4).Takahashi D, Wada H, Ogita M, Yasuda K, Nishio R, Takeuchi M, Shitara J, Tsuboi S, Dohi T, Suwa S, Miyauchi K, Daida H, Minamino T. Impact of Lipoprotein(a) as a Residual Risk Factor in Long-Term Cardiovascular Outcomes in Patients With Acute Coronary Syndrome Treated With Statins. Am J Cardiol, 2022; 168: 11-16. [DOI] [PubMed] [Google Scholar]
- 5).Tomoi Y, Takahara M, Soga Y, Kodama K, Imada K, Hiramori S, Ando K. Impact of High Lipoprotein(a) Levels on Clinical Outcomes Following Peripheral Endovascular Therapy. JACC Cardiovasc Interv, 2022; 15: 1466-1476 [DOI] [PubMed] [Google Scholar]
- 6).Tada H, Kojima N, Yamagami K, Takeji Y, Sakata K, Usui S, Kawashiri MA, Takamura M. Association Between Lipoprotein (a) Levels and Coronary Artery Disease (CAD) Among Patients With or Without CAD Family History. J Lipid Atheroscler, 2025; 14: 120-127 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7).Dai K, Shiode N, Yoshii K, Kimura Y, Matsuo K, Jyuri Y, Tomomori S, Higaki T, Oi K, Kawase T, Sairaku A, Ohashi N, Suenari K, Nishioka K, Masaoka Y, Nakano Y. Impact of Lipoprotein (a) on Long-Term Outcomes in Patients With Acute Myocardial Infarction. Circ J, 2023; 87: 1356-1361 [DOI] [PubMed] [Google Scholar]
- 8).Funabashi S, Kataoka Y, Hori M, Ogura M, Doi T, Noguchi T, Harada-Shiba M. Characterization of Polyvascular Disease in Heterozygous Familial Hypercholesterolemia: Its Association With Circulating Lipoprotein(a) Levels. J Am Heart Assoc, 2022; 11: e025232 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9).Murai K, Kataoka Y, Ray KK, Funabashi S, Hori M, Ogura M, Doi T, Makino H, Noguchi T, Harada-Shiba M. Corneal arcus and Achilles tendon thickness reflect circulating lipoprotein(a) levels in familial hypercholesterolemia: Implication for predicting future cardiovascular events. J Clin Lipidol, 2025; 19: 1273-1283 [DOI] [PubMed] [Google Scholar]
- 10).Shishikura D, Harada-Shiba M, Michikura M, Fujioka S, Fujisaka T, Morita H, Kanzaki Y, Hoshiga M. Clinical Impact of Lipoprotein (a) and Cumulative Low-Density Lipoprotein Cholesterol Exposure on Coronary Artery Disease in Patients with Heterozygous Familial Hypercholesterolemia. J Atheroscler Thromb, 2025; 32: 100-110 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11).Yoshida H, Kroes M, Sakai Y, Takahashi Y, Yamanaka Y, Crawford B, Ako J. Lipoprotein(a) in Japanese Patients With Cardiovascular Disease: A Systematic Review. JACC Asia, 2025: 1525-1539 [DOI] [PMC free article] [PubMed] [Google Scholar]