Prof Derick Raal, University of the Witwatersrand, Johannesburg, South Africa
The last decade has seen a resurgence of interest in lipoprotein(a) [Lp(a)], the mysterious brother of LDL (low-density lipoprotein). Indeed, there is now established evidence that Lp(a) is an independent risk factor for cardiovascular disease (CVD). Meta-analyses of large prospective observational studies together with Mendelian randomization studies demonstrated that elevated plasma Lp(a) levels are associated with an increased risk for atherosclerotic CVD, as well as the development of aortic stenosis.1Importantly, these associations appear to be independent of LDL cholesterol.
There are, however, some paradoxes which have not been fully explained. First, the association with CVD has been questioned in some ethnic groups. For example, atherosclerotic CVD remains uncommon in the black African population despite mean Lp(a) levels that are approximately two-fold higher than in Caucasian populations. Aortic stenosis, other than that due to rheumatic heart disease, is also uncommon in black Africans.2 Second, there is uncertainty that lowering Lp(a) translates to clinical benefit. Several large randomized clinical trials with therapies that lower Lp(a) by 20-30% such as niacin and the PCSK9-inhibitors, have not provided conclusive evidence that lowering Lp(a) reduces the risk for CVD events.How can the paradox exemplified by these trials be explained? Could there be an interaction between Lp(a) and LDL cholesterol so that elevated Lp(a) causes CVD mainly in individuals with high LDL cholesterol levels, as has been suggested by some?3,4
And if this is the case, is lowering elevated Lp(a) still relevant when LDL cholesterol is low? The question is especially pertinent in the era of novel LDL-lowering treatments such as the PCSK9 inhibitors, which have the capacity to lower Lp(a) below current guideline-recommended goals. A new report based on two large population studies, the European Prospective Investigation of Cancer (EPIC)-Norfolk study (n=16,654) and the Copenhagen City Heart Study (CCHS, n=9448), which correspond to a primary prevention setting, sheds some light on this question.5
In this analysis, individuals were categorized according to their Lp(a) and LDL cholesterol levels. Cut-offs for Lp(a) were based on the 80thpercentile for Lp(a), and LDL cholesterol cut-offs were set at 2.5, 3.5, 4.5, and 5.5 mmol/L. As cholesterol associated with Lp(a) is known to contribute to LDL cholesterol levels, the investigators used an Lp(a)-corrected LDL cholesterol to avoid a disproportionate impact of Lp(a) cholesterol, especially in individuals with low LDL cholesterol. Multivariable-adjusted Hazard ratios used the group with corrected LDL cholesterol <2.5 mmol/L and Lp(a) <80th cohort percentile as the reference.
The investigators showed that Lp(a) levels above the 80th percentile cut-off were associated with increased CVD risk compared with lower Lp(a) levels, if LDL cholesterol levels were concomitantly 2.5 mmol/L or higher. However, when LDL cholesterol levels were lower, CVD risk associated with elevated Lp(a) levels was attenuated.5 These findings would suggest that potent LDL cholesterol lowering is the primary target to lower absolute risk also in individuals with elevated Lp(a).
What are the implications of this analysis for the paradoxes outlined above? First, while LDL cholesterol levels are increasing in Africa because of the adoption of a Western lifestyle, levels still remain lower than those observed in Western populations. Thus, there is the possibility that any potential benefit from Lp(a) lowering is attenuated in this group.
Second, the report has important ramifications for clinical trials testing novel Lp(a)-lowering therapies. The findings imply that large absolute reductions in Lp(a) are required for clinical benefit. In fact, a recent analysis of five Mendelian randomization studies which evaluated this question, indicated that reduction in Lp(a) by at least 100 mg/dl is needed to achieve a clinically meaningful reduction in CVD risk.6Bearing this and the current report in mind, it is clear that studies will need to to select the right cohort to evaluate whether lowering Lp(a) with highly potent therapies specifically targeting Lp(a) will reduce CVD event rates independently of lowering LDL cholesterol.
- Nordestgaard BG, Langsted A. Lipoprotein(a) as a cause of cardiovascular disease: insights from epidemiology, genetics and biology. J Lipid Res 2016;57:1953-75. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/27677946
- Kronenberg F, Utermann G. Lipoprotein(a): resurrected by genetics. J Intern Med 2013;273:6-30. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/22998429
- Afshar M, Pilote L, Dufresne L et al. Lipoprotein(a) interactions with low-density lipoprotein cholesterol and other cardiovascular risk factors in premature acute coronary syndrome (ACS). J Am Heart Assoc 2016;5:e003012–e003019. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/27108248
- Suk Danik J, Rifai N, Buring JE, Ridker PM. Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women. JAMA 2006;296:1363–70. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/16985228
- Verbeek R, Hoogeveen RM, Langsted A, et al. Cardiovascular disease risk associated with elevated lipoprotein(a) attenuates at low low-density lipoprotein cholesterol levels in a primary care setting. Eur Heart J 2018; 39:2589-96. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/29931232
- Burgess S, Ference BA, Staley JR et al. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies. A Mendelian Randomization analysis. JAMA Cardiol doi:10.1001/jamacardio.2018.1470. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/29926099