After low density lipoprotein cholesterol (LDL-C) has been targeted to reduce cardiovascular disease (CVD) risk, other novel lipid biomarkers have become the center of attention of investigation, and on-going clinical trials are targeting these lipid markers trying to lower the so-called "residual CVD risk" in addition to conventional lipid-lowering therapy. Among them, serum lipoprotein(a) [Lp(a)] is being widely discussed. Numerous epidemiological and pathophysiological studies have suggested the causal association of high serum Lp(a) and elevated CVD risk.^1-4 Recently more detailed investigations emerged regarding the potential heterogenous relationship of Lp(a) and CVD among different populations. They try to answer the question: "Lp(a) appears bad for CVD, but is it universally bad to everyone?". While this has been largely explored among Western countries, data from Asian populations is relatively lacking: a Korean study previously found elevated Lp(a) level was an independent predictor of the development of CVD in Korean patients with type 2 diabetes mellitus.⁵ Xu et al. also found that Lp(a) was positively associated with recurrent CVD risk after percutaneous coronary intervention (PCI) for Chinese patients with chronic kidney disease.⁶ A recent study from China added important evidence on the association of Lp(a), diabetes status and CVD among Chinese with subclinical coronary artery disease (CAD).⁷

A new study by Jin et al. included 5,143 patients from 2011 to 2015 from three medical centers in China who were found to have CAD on angiography (coronary stenosis >= 50% of at least one coronary artery) but no clinical coronary events. The patients were classified into normal glucose, pre-diabetes and diabetes mellitus (DM) group and further into four Lp(a) groups at baseline. They were then followed up for CVD events, including cardiovascular mortality, nonfatal myocardial infarction and stroke, for a median of 6.1 years. Despite the presence of angiography-proven CAD among the participants, most of them received lipid, blood pressure and glucose treatment at baseline and the overall modifiable risk profiles were acceptable. In the study, either DM status or Lp(a) groups alone were associated with CVD risk; DM combined with high level of Lp(a) had the highest risk of CVD; when Lp(a) was examined within each DM-defined group, Lp(a) appeared to be more strongly associated with CVD among DM and pre-DM than the normal glucose group. The researchers further examined the incremental predictive value of Lp(a) for CVD among the three DM groups: when added to traditional risk factors, Lp(a) significantly improved the C-statistics of CVD prediction model among the DM patients (0.704 vs. 0.675, p=0.001) while the improvement was modest in pre-DM group (0.722 vs. 0.700, p=0.043) and no different in normal glucose metabolism group (0.769 vs. 0.770, p=0.876).

In North American populations, we previously showed that Lp(a) levels were the most significant predictor of atherosclerotic cardiovascular disease (ASCVD) among those with prior CVD history. The work of Jin et al. once again demonstrate that Lp(a) remains an important predictor for future CVD events among Asian patients with subclinical CAD, especially for those with abnormal glucose metabolism. Patients with both CAD and DM are considered to have higher CVD risk and therefore receive more preventive therapies, which may interfere the natural association of corresponding risk factors and CVD risk. Therefore, the traditional modifiable risk factors may not discriminate CVD risk as well as in their non-DM counterparts and this might help explain the larger model improvement by adding Lp(a) in the DM group. The identification of the novel prognostic lipid measure for CVD has several implications: first, Lp(a) might be used as a risk restratification tool when CVD risk assessment is unclear using conventional risk factors. Even among those with relatively high CVD risk, Lp(a) may still be useful in further risk stratification and help improve the cost-effectiveness of other treatments by lowering the number needed to treat. Lp(a) may also be a promising target for preventive therapy. PCSK9 inhibitors as one of the Lp(a)-lowering medications now shows positive efficacy on reducing CVD risk and the related clinical trials are now underway in various populations including the Asians.⁸ Other selective or non-selective Lp(a)-lowering therapies such as antisense oligonucleotides and lipoprotein apheresis are also in early-stage clinical trial.⁹ All these investigations will potentially make Lp(a) the next promising CVD risk assessment tool and future CVD risk reduction target.

It should be noted that the study population came from the top hospitals in Beijing China, whose patients tended to be largely treated as implied in their paper. Thus, the generalizability of conclusion to the whole Chinese/Asian people should be carefully considered. Future research may seek to include more diverse and larger data resources to expand the transportability and generalizability of their findings.

References

1. Emerging Risk Factors Collaboration, Ergou S, Kaptoge S, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009;302:412-23.
2. Erqou S, Thompson A, Di Angelantonio E, et al. Apolipoprotein(a) isoforms and the risk of vascular disease: systematic review of 40 studies involving 58,000 participants. J Am Coll Cardiol 2010;55:2160-67.
3. Craig WY, Neveux LM, Palomaki GE, Cleveland MM, Haddow JE. Lipoprotein(a) as a risk factor for ischemic heart disease: metaanalysis of prospective studies. Clin Chem 1998;44:2301-6.
4. Boffa MB, Marcovina SM, Koschinsky ML. "Lipoprotein (a) as an emerging risk factor for atherothrombosis." In: Davidson M, Togh PP, Maki KC, eds. Therapeutic Lipidology. New Jersey: Humana Press Inc; 2007:241-66.
5. Lim TS, Yun JS, Cha SA, et al. Elevated lipoprotein(a) levels predict cardiovascular disease in type 2 diabetes mellitus: a 10-year prospective cohort study. Korean J Intern Med  2016;31:1110-19.
6. Xu N, Tang XF, Yao Y, et al. Association of plasma lipoprotein(a) with long-term adverse events in patients with chronic kidney disease who underwent percutaneous coronary intervention. Am J Cardiol  2018;122:2043-48.
7. Jin JL, Cao YX, Zhang HW, et al. Lipoprotein(a) and cardiovascular outcomes in patients with coronary artery disease and prediabetes or diabetes. Diabetes Care 2019;42:1312-18.
8. Lorenzatti AJ, Eliaschewitz FG, Chen Y, et al. Randomised study of evolocumab in patients with type 2 diabetes and dyslipidaemia on background statin: Primary results of the BERSON clinical trial. Diabetes Obes Metab 2019;21:1455-63.
9. Saeed A, Virani SS. Lipoprotein(a) and cardiovascular disease: current state and future directions for an enigmatic lipoprotein. Front Biosci (Landmark Ed) 2018;23:1099-112.

Keywords: Metabolic Syndrome, Lipoprotein(a), Coronary Artery Disease, Risk Factors, Cholesterol, LDL, Diabetes Mellitus, Type 2, Blood Pressure, Cost-Benefit Analysis, Oligonucleotides, Antisense, Glucose, Coronary Angiography, Myocardial Infarction, Risk Assessment, Stroke, Coronary Stenosis, Percutaneous Coronary Intervention, Renal Insufficiency, Chronic, Risk Reduction Behavior, Blood Component Removal

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