Can Lipoprotein (a) Stand Alone as a Atherosclerotic Risk Factor?
Lipoprotein (a) [Lp(a)] is a low density lipoprotein (LDL) — like particle that is associated with increased risk of atherosclerotic cardiovascular disease (ASCVD). (1) Lp(a) levels are primarily genetically determined. Lp(a) carries cholesterol ©, but also has thrombotic and inflammatory characteristic, so could contribute to ASCVD via its atherosclerotic, thrombotic or inflammatory properties.(1) Lp(a) is considered a “risk enhancer” by the 2018 Cholesterol Management Guidelines.(2) There are presently no lipid lowering agents specifically approved to lower Lp(a), but measuring Lp(a) routinely may help determine how aggressively to lower a patient’s LDL-C. Measuring Lp(a) may also be valuable with worried patients, who have good lipid levels but a family history of ASCVD. I measure Lp(a) in that situation to avoid providing “false reassurance” based on their good lipid levels alone.
Zhang and colleague used data from 4,679 participants in the Multi Ethnic Study of Atherosclerosis or MESA study to examine the relationship between Lp(a), high sensitivity CRP (hsCRP) and ASCVD.(3) These authors divided the MESA participants into 3 Lp(a) groups: <50, 50–99, and ≥100 mg/dl. Increasing Lp(a) was only associated with increased ASCVD risk when the hsCRP also elevated ≥2 mg/L. The ACCELERATE or Assessment of Clinical effects of Cholesterol Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes trial also found that Lp(a) increased recurrent ASCVD risk only when the CRP was >2 mg/L.(4)
These results imply that Lp(a) only matters if there is concomitant inflammation, and suggests that Lp(a) should only be measured, and used to determine treatment approaches, only if the hsCRP >2 mg/dl. I am not a statistician, but here is my concern. This is not really a study about the people we worry about, those with really high Lp(a). According to Figure 1, 3,748 (80%) of the study population had Lp(a) values <50, and only 196 (4%) had values ≥100 mg/dl. There were also few events in this high Lp(a) group. So, these data are provocative, but may not have had enough high Lp(a) patients to address all the true risk of Lp(a). We probably need bigger studies with more very high Lp(a) subjects as well as results from the Lp(a) treatment trials to know for sure whether Lp(a) can stand on its own as a ASCVD risk factor. In the interim, Lp(a) remains a risk enhancer and maybe of some use in making clinical decisions.
1. Tsimikas,S. A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. J Am Coll Cardiol. 2017;69(6):692–711.
2. Grundy, SM, et al.2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73(24):e285-e350.
3. Zhang, W et. al. High-Sensitivity C-Reactive Protein Modifies the Cardiovascular Risk of Lipoprotein(a): Multi-Ethnic Study of Atherosclerosis. J Am Coll Cardiol. . 2021;78(11):1083–1094.
4. Puri R, et al. Effect of C-reactive protein on lipoprotein(a)-associated cardiovascular risk in optimally treated patients with high-risk vascular disease: a prespecified secondary analysis of the ACCELERATE Trial. JAMA Cardiol. 2020;5(10):1136–1143.
This was also published in Practice Update Commentaries.
