A single measurement of lipoprotein(a) molar concentration is an efficient marker informing coronary artery disease (CAD) risk, regardless of statin use, according to a new publication. The findings, based on data from more than 15,000 unrelated UK Biobank participants with repeat measurements of lipoprotein(a) were published Monday online ahead of the Feb. 22 issue of the Journal of the American College of Cardiology. Many traditional cardiovascular risk factors come with temporal variability when measured, said the authors, led by Mark Trinder, MSc, from the University of British Columbia and Broad Institute of Harvard. Lipoprotein(a) – a low-density lipoprotein (LDL) that transports cholesterol in the blood – is known to be a potentially causal risk factor for multiple cardiovascular diseases including CAD, heart failure, ischemic stroke, aortic stenosis and all-cause mortality. The molar concentration of the low-density lipoprotein is believed to “fully explain” the associated cardiovascular risk, the researchers added. However, whether there is temporal variability in lipoprotein(a) has remained poorly understood; therefore, it has been unclear whether repeat testing could help refine risk prediction, they said. The current study set out to examine the stability of lipoprotein(a) concentration in molars, with a particular focus on risk of incident CAD, and whether statins have any significant effect on molar concentration. Data from the UK Biobank – a prospective observational study of approximately 500,000 volunteer adults aged 40-69 years – was collected across 22 U.K. sites between 2006 and 2010, with follow-up ongoing. Baseline lipoprotein(a) measurements were correlated with first follow-up measurements in 16,017 participants, and incident CAD was assessed among 15,432 using Cox proportional hazards models. The measurements were significantly correlated over a median of 4.42 years (interquartile range [IQR]: 3.69-4.93 years; Spearman rho = 0.96; P < 0.0001). Median lipoprotein(a) molar concentration was 19.50 nmol/L at baseline (IQR: 7.56-72.50 nmol/L), and 20.40 nmol/L at follow-up (IQR: 7.70-77.50 nmol/L). Further, the correlation between baseline and follow-up measurements remained stable across “time between” measurements of <3 years (rho = 0.96), 3 to 4 years (rho = 0.97), 4 to 5 years (rho = 0.96) and >5 years (rho = 0.96). Yet, despite this relative stability, some participants still displayed differences between baseline and follow-up lipoprotein(a) measurements that were “quite large (ie, >120 nmol/L),” the authors noted. Follow-up measurements also tended to be greater than baseline lipoprotein(a), with 8.66% of participants showing follow-up measurements at least a 25 nmol/L increase, while only 4.12% had follow-up measurements at least 25 nmol/L less than baseline. “Although some individuals did display relatively large differences between follow-up and baseline lipoprotein(a) measures, these differences did not associate with increased risk of incident CAD because these changes largely persisted within the abnormal range, ie, among individuals with elevated lipoprotein(a),” the authors concluded. On whether cholesterol-lowering medications such as statins have an effect on molar lipoprotein(a) concentration – a potential phenomenon for which the evidence remains “mixed” – the authors sought to compare mean percent change between those on medication and those who were not. As a positive control, they also assessed the change in low-density lipoprotein-cholesterol (LDL-C) levels associated with use of cholesterol-lowering medication. Although starting statin medication after baseline showed a significant decrease in the mean percent change in LDL-C levels (P < 0.0001), there was no significant difference in the mean percent change in lipoprotein(a) molar concentration from baseline to follow-up between those starting statin medication after baseline and those either “not naïve” to statins, discontinuing cholesterol-lowering regimes before follow-up, or who continued statin use throughout (P = 0.25). The authors also sought to answer whether instability in molar lipoprotein(a) concentration was associated with cardiovascular risk. Follow-up lipoprotein(a) molar concentration was significantly associated with risk of incident CAD (hazard ratio [HR] per 120 nmol/L: 1.32 [95% CI: 1.16-1.50]; P = 0.0002). However, the delta between follow-up and baseline lipoprotein(a) molar concentration was not significantly associated with incident CAD independent of follow-up lipoprotein(a) (P = 0.98). The authors concluded: “These findings suggest that longitudinal measurements of lipoprotein(a) are likely unnecessary for cardiovascular risk assessment in the context of primary prevention because the molar concentration of lipoprotein(a) is generally stable, regardless of statin use. “It is possible that these conclusions could be different for individuals with prevalent atherosclerotic cardiovascular disease who are at higher risk of recurrent cardiovascular events.” They called for further research to define clinical practice algorithms utilizing a single accurate measurement of lipoprotein(a) molar concentration to detect and manage patients at risk of CAD. Questions remaining However, the results do not necessarily translate to individuals in secondary prevention “where fluctuations in [lipoprotein(a)] are more pronounced” since the Biobank enrolled participants free of clinical cardiovascular disease at entry, according to editorialists. Santica M. Marcovina, ScD, PhD, from the Medpace Reference Laboratories, Cincinnati, and Michael D. Shapiro, DO, MCR, from Wake Forest University School of Medicine, also stressed that “patients with manifest [atherosclerotic cardiovascular disease] more frequently use high-intensity statin therapy and more commonly have elevated baseline [lipoprotein(a)] levels, both of which may accentuate measurement variability.” Nevertheless, they stressed the importance of establishing a lipoprotein(a) screening program as set out in the paper. With no currently approved treatments to lower lipoprotein(a) and potentially greater than 1.5 billion individuals with at-risk levels, a “once in a life-time” screening test should be implemented as soon as possible, they urged. “All current analytical methods, particularly those based on a 5-point calibration approach as used in this paper, appear to be well-suited to assess ASCVD risk in the general population,” they said. Sources: Trinder M, Paruchuri K, Haidermota S, et al. Repeat Measures of Lipoprotein(a) Molar Concentration and Cardiovascular Risk. J Am Coll Cardiol 2022;79:617-628. Marcovina SM, Shapiro MD. Measurement of Lipoprotein(a): A Once in a Lifetime Opportunity. J Am Coll Cardiol 2022;79:629-631. Image Credit: 7activestudio – stock.adobe.com