Author + information
- †South Australian Health and Medical Research Institute, University of South Australia, Adelaide, Australia
- ‡Discipline of Medicine, University of Adelaide, Adelaide, Australia
- §School of Population Health, University of South Australia, Adelaide, Australia
- ↵∗Reprint requests and correspondence:
Dr. Stephen Nicholls, South Australian Health and Medical Research Institute, P.O. Box 11060, Adelaide, South Australia, 5001, Australia.
Despite the established benefits of randomized controlled trials in the primary and secondary prevention settings, atherosclerotic cardiovascular disease continues to present a major public health challenge throughout the world. Beyond the critical, often overlooked importance of lifestyle measures, new efforts to improve disease prevention will require more effective approaches to tailor risk assessment and subsequently to modify that risk. The successful targeting of low-density lipoprotein cholesterol (LDL-C) represents a model on which to base these future developments. The findings that LDL-C levels are directly associated with cardiovascular risk and that lowering its levels results in fewer clinical events underscore the importance of LDL-C in strategies designed to prevent cardiovascular disease (1).
However, the findings that many persons judged to be not at high risk by standard risk prediction models experience clinical events (2) and that adverse cardiovascular outcomes continue to be observed in patients who undergo intensive modification of traditional risk factors (3) suggest an urgent need to develop additional approaches to risk stratification. Although ongoing studies are evaluating LDL-C–lowering strategies in addition to statins, attention also has turned to a range of other lipid factors implicated in atherosclerotic disease. High-density lipoprotein cholesterol (HDL-C) continues to be a challenge, given inconsistencies in reports of protection from heart disease, in terms of both association with risk (4) and the lack of efficacy of HDL-C–raising therapies (5,6). Increasing evidence implicates an independent role for measurements of triglycerides (7), as well as remnant lipoprotein particles (8), in risk prediction. However, the demonstration that lowering the levels of these substances translates to clinical benefit remains to be established.
In parallel, lipoprotein (a), abbreviated Lp(a), continues to receive considerable attention with regard to its potential role in promoting atherosclerosis and its role in risk reduction strategies. Lp(a) has unique structural properties that combine stimulatory effects on atherogenic and thrombotic pathways that underlie the pathogenesis of acute ischemic events (9). In this issue of the Journal, Willeit et al. (10) report findings of their investigation on the capability of Lp(a) levels to discriminate cardiovascular risk over a 15-year period in the Bruneck Study. In this community-based study of 826 men and women who were 45 to 84 years old, a direct relationship was observed between Lp(a) levels and the subsequent incidence of major adverse cardiovascular events. This finding supports a growing body of evidence linking Lp(a) levels and cardiovascular risk. Most importantly, however, the current analysis provides compelling evidence to support a potential role of Lp(a) in reclassification of patients previously determined to be at intermediate cardiovascular risk on the basis of traditional algorithms. In fact, nearly 2 in 5 of such patients underwent restratification to either lower or higher cardiovascular risk settings.
Although these observations are of potential interest in expanding the clinical use of Lp(a), certain issues remain unresolved. Do such findings influence the integration of Lp(a) testing into risk prediction algorithms? In general, the use of this testing is not widespread; it tends to be confined to subsets of patients, including those with premature coronary disease in the absence of any major cardiovascular risk factor. Whether systematic screening of Lp(a) will be of clinical benefit will ultimately require validation that it changes practice and clinical outcomes in a cost-effective manner. Such studies have not been performed. Similarly, the relative utility of serial evaluation of Lp(a) is untested. Increasing evidence has highlighted the potential differences between Lp(a) isoforms with regard to their relationship with cardiovascular risk (9). Of particular interest, no such association was demonstrated in the current analysis beyond the predictive capability of Lp(a) levels.
Ultimately, we need to ask how such measurements will change clinical practice. In an ever-changing world of lipid guidelines, some countries will use Lp(a) to identify higher-risk patients, whereas other countries, wanting to adhere more closely to evidence from randomized clinical trials, will find an absence of data. Most physicians who routinely measure Lp(a) levels will use such results for triage of patients to more intensive use of established preventive therapies. The finding that Lp(a) levels tend to be less predictive of cardiovascular outcomes in patients with very low LDL-C levels supports, but does not validate, the use of more intensive statin therapy (11). The concept of developing agents that specifically lower Lp(a) levels and in turn reduce event rates is attractive. Disappointingly, estrogen and nicotinic acid both lower Lp(a), among their other actions, yet they did not reduce cardiovascular event rates in clinical trials. Experimental therapies with, for example, cholesteryl ester transfer protein (CETP) and proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors lower Lp(a), but any potential clinical benefit is likely derived from other lipid effects. Whether a more selective Lp(a)-lowering strategy will prove protective remains to be tested.
This body of evidence supports a potential role for Lp(a) as both a risk marker and a target for therapeutic lowering. Whether Lp(a) will identify the patient with modifiable cardiovascular risk is unknown. The field is in great need of clinical trials to determine the optimal use of Lp(a). As a result, the journey of Lp(a) toward routine use continues.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Nicholls has received research support from AstraZenecahttp://dx.doi.org/10.13039/100004325, Eli Lilly, Cerenis, Anthera, Omthera, Rochehttp://dx.doi.org/10.13039/100004337, Novartishttp://dx.doi.org/10.13039/100004336, Resverlogix, InfraReDx, Amgenhttp://dx.doi.org/10.13039/100002429, and LipoScience; and is a consultant for AstraZeneca, Boehringer Ingelheim, CSL Behring, Merck, Takeda, Roche, Omthera, Novartis, Amgen, Sanofi-Aventis, and Eli Lilly. Dr. Brown has reported that he has no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Lloyd-Jones D.M.
- Libby P.
- Chapman M.J.,
- Ginsberg H.N.,
- Amarenco P.,
- et al.
- Varbo A.,
- Benn M.,
- Tybjaerg-Hansen A.,
- Nordestgaard B.G.
- Nordestgaard B.G.,
- Chapman M.J.,
- Ray K.,
- et al.
- Willeit P.,
- Kiechl S.,
- Kronenberg F.,
- et al.
- Nicholls S.J.,
- Tang W.H.,
- Scoffone H.,
- et al.