Reconsider lipoprotein(a) thresholds for residual risk in Japanese patients
September 2026
Elevated lipoprotein (a)[Lp(a)] is a contributor to residual cardiovascular risk despite intensive lowering of low-density lipoprotein cholesterol. This report from the Lp(a)-Japan study reaffirms this and indicates that Lp(a) thresholds may differ between Japanese and Caucasian individuals with coronary heart disease.
Kataoka Y, Ray KK, Nicholls SJ, et al. Lipoprotein(a) and residual cardiovascular risks in Japanese patients with coronary artery disease who achieve guideline-recommended low-density lipoprotein cholesterol goals. Eur Heart J 2026; doi.org/10.1093/eurheartj/ehag446.
STUDY SUMMARY
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Objective |
This study investigated a) whether elevated Lp(a) concentration is a residual risk factor in Japanese patients with coronary artery disease (CAD) and b) whether lowering low-density lipoprotein cholesterol (LDL-C) to <55 mg/dL mitigates this risk.
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Study design |
The Lp(a)JAPAN study (Japan [Lp(a) and Cardiovascular Outcomes following Guideline Recommended LDL-C Control in JAPANese Patients with CAD) was a multicentre, retrospective observational study conducted at three sites in Japan .
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Study population |
Japanese patients with CAD requiring percutaneous coronary intervention (PCI), with Lp(a) and LDL-C measurements 2 months after PCI, and at least 3 years follow-up data after PCI. LDL-C levels were managed according to guidelines from the 2022 Japanese Circulation Society and the 2022 Japan Atherosclerosis Society.
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Main study variables |
The primary outcome was major adverse cardiovascular events (MACE), a composite of cardiac death, nonfatal myocardial infarction and clinically driven coronary revascularisation in non-culprit segments.
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Methods |
LDL-C and Lp(a) levels were measured 2 months after PCI; the corresponding LDL-C level was defined as the ‘achieved LDL-C level’ and was used to stratify patients. Lp(a) was measured in mg/dL; assays that report in molarity are now preferred. The risk of MACE was compared according to Lp(a) levels (<30, ≥30 and <50 mg/dL, and ≥50 mg/dL) and amongst LDL-C strata (<55 mg/dL vs ≥55 mg/dL) 2 months after PCI.
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Key results |
In total 3516 patients underwent PCI, of whom 1581 (mean age 68.3 years, 23.6% female) had Lp(a) data and at least 3 years follow-up. Overall, the median Lp(a) was 12.8 mg/dL (interquartile range: 6.3–29.4 mg/dL) and mean LDL-C was 59 ± 12 mg/dL. The proportion of patients with Lp(a) < 30 mg/dL, ≥30 and <50 mg/dL, and ≥50 mg/dL overall was 76.3% (1206 of 1581), 11.9% (189 of 1581), and 11.8% (186 of 1581), respectively. Among the study group, 512 had achieved LDL-C levels <55 mg/dL and 1069 had achieved LDL-C levels ≥55 mg/dL.
Over the 5.1-year observation period, MACE occurred in 274 (17.3%) patients. Irrespective of achieved LDL-C, elevated Lp(a) levels identified those patients at higher risk (Table 1). For the group achieving LDL-C <55 mg/dL, standardised 5-year MACE rates increased in association with increasing Lp(a) levels, from 5.0% at Lp(a) <30 mg/dL, to 17.0% for Lp(a) ≥30 and <50 mg/dL, and 33.4% for Lp(a) ≥ 50 mg/dL.
Table 1. Risk of MACE according to achieved LDL-C and Lp(a)
Receiver operator curve analysis indicated that among patients with achieved LDL-C <55 mg/dL, the threshold Lp(a) value for increased risk was 28.2 mg/dL. Overall, about one in 5 patients had Lp(a) values above this threshold: 23.8% (254 of 1069) in patients with achieved LDL-C ≥55 mg/dL and 20.1% (103 of 512) in patients with LDL-C <55 mg/dL.
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Author conclusions |
Whilst lower achieved LDL-C attenuates in part the risk from Lp(a), elevated Lp(a) levels still associate with worse cardiovascular outcomes. The Lp(a) threshold amongst Japanese patients with CAD at risk of recurrent events appears lower than in Caucasian populations which merits further evaluation. |
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Comment
Extensive evidence, largely derived from observational and genetic studies, supports Lp(a) as an independent and causal risk factor for atherosclerotic cardiovascular disease and aortic valve stenosis (1). Expert consensus has concluded that there is a continuous association between Lp(a) and risk for atherosclerotic cardiovascular disease (1). The current study affirms the importance of elevated Lp(a) as a contributor to residual cardiovascular risk in Japanese patients with CAD and well controlled LDL-C levels (<55 mg/dL), consistent with a recent meta-analysis (2). In these patients, standardised 5-year MACE rates were 5.0% in patients with Lp(a) <30 mg/dL, and increased to 17.0% in patients with Lp(a) ≥30 and <50 mg/dL, and 33.4% in those with Lp(a) ≥ 50 mg/dL. Thus, even at lower Lp(a) levels, cardiovascular risk was increased.
While there is currently no target for Lp(a), European and US guidelines associate an Lp(a) level >50 mg/dL (125 mol/L) with increased cardiovascular risk (3,4), the current study showed that risk was already increased at lower levels even if LDL-C was well controlled. Indeed, an Lp(a) level ≥28.2 mg/dL was identified as the threshold for increased risk for MACE in Japanese patients with LDL-C <55 mg/dL. About one in five of these patients had Lp(a) values above this threshold; about half had elevated Lp(a) below the 50 mg/dL risk threshold recommended by guidelines. Thus, there is a high burden of patients with mildly elevated Lp(a) levels even among those with well controlled LDL-C.
Despite the limitations of a retrospective study design, the inclusion of CAD patients undergoing PCI who may not be representative of a wider population of Japanese patients with atherosclerotic cardiovascular disease, and measurement of Lp(a) in mg/dL rather than molarity which is preferred (1), the study has important conclusions. First, the study reaffirms the continuing relationship of elevated Lp(a) with residual risk for cardiovascular events despite well controlled LDL-C levels. Second, the study highlights the need for further investigation to define Lp(a)-associated risk thresholds in patients of different ancestry.
References
- Kronenberg F, Mora S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J 2022;43:3925-46.
- Bhatia HS, Wandel S, Willeit P, et al. Independence of lipoprotein(a) and low-density lipoprotein cholesterol-mediated cardiovascular risk: a participant-level meta-analysis. Circulation 2025;151:312–21.
- Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111–88.
- Blumenthal RS, Morris PB, Gaudino M, et al. ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2026;87:2624–757.
Key words: Lipoprotein(a); residual cardiovascular risk; threshold; Japanese study
