Author + information
- Stephen J. Nicholls, MBBS, PhD∗ ( and )
- Peter J. Psaltis, MBBS, PhD
- ↵∗Reprint requests and correspondence:
Dr. Stephen J. Nicholls, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, South Australia 5001, Australia.
Atherogenic forms of cholesterol continue to play a central role in our approach to the prevention of cardiovascular disease (CVD). Whereas risk prediction algorithms are increasingly focusing on global risk for patients, elevated cholesterol levels continue to identify patients more likely to experience cardiovascular events, and outcome trials have consistently demonstrated that lowering low-density lipoprotein cholesterol (LDL-C) with statins has a favorable impact on clinical events. However, the finding that cardiovascular risk persists in many patients, despite appropriate use of lipid lowering has fueled the search to identify additional factors for modulation in preventive strategies (1).
High-density lipoproteins (HDL) represent one such approach on the basis that their functional properties are thought to convey a potentially protective influence on the artery wall. Numerous population studies have demonstrated an inverse association between high-density lipoprotein cholesterol (HDL-C) levels and prospective cardiovascular risk (2). Furthermore, the presence of low HDL-C levels in patients treated with high-intensity statins continues to portend an ongoing accelerated risk of cardiovascular events (3). Such findings have stimulated the search to develop agents that raise HDL-C as a logical approach to reducing this residual risk. However, the contemporary era has witnessed the disappointing results of major clinical trials, in which therapeutic approaches to HDL-C raising with niacin (4) and cholesteryl ester transfer protein inhibitors (5,6) have failed to beneficially lower cardiovascular event rates compared with standard of care alone. Whereas these agents have many functional effects, the failure to produce any clinical benefit in these studies has brought into question not only the concept of HDL-C raising, but the HDL hypothesis in general. This concern has been supported by findings from Mendelian randomization studies demonstrating that polymorphisms regulating HDL-C levels do not associate with cardiovascular risk, suggesting that HDL-C does not play a causal role in atherosclerosis (7).
In this issue of the Journal, Ko et al. (8) provide further evidence that will continue to dampen the enthusiasm of a protective link between HDL and clinical risk. Studying 631,762 individuals without manifest CVD in the CANHEART (Cardiovascular Health in Ambulatory Care Research Team), they reported that low HDL-C levels were associated with a greater risk of death due to cardiovascular, cancer, or other causes, whereas very high HDL-C levels were associated with a greater risk of noncardiovascular death. As anticipated, low HDL-C levels were associated with lifestyle and comorbidity factors that in their own right portend greater cardiovascular risk. Given these complex associations, the investigators concluded that HDL-C is unlikely to represent a cardiovascular specific risk factor of value in targeting for therapeutic modification.
The findings of CANHEART highlight the opportunity to ask important questions within large, linked datasets of real world clinical information. CANHEART involved the integration of a number of databases, enabling investigation of the factors that associate with adverse clinical outcomes. This represents the evolution in clinical observations, which span the spectrum including anecdotal case reports, small hospital audits, large multicenter registries, and ultimately the study of large health systems. Linking recorded real-world data will permit not only the ability to make seminal observations of factors influencing changes in the natural history of disease, but also the ability to perform innovative clinical trials and evaluate the uptake of established interventions from both an efficacy and safety perspective. The emergence of big data approaches to clinical research presents a transformative opportunity. The health care systems that choose to be early adopters and embrace these opportunities stand to gain considerable advances in their ability to modify health care outcomes.
So what does the current finding imply with regard to the role of HDL-C in CVD? Does the conclusion by Ko et al. (8) that HDL-C is unlikely to be of value as a modifiable target suggest that any HDL-targeted therapies are likely to be futile? It is fair to acknowledge that in the statin era, no agent that substantially elevates HDL-C levels has been demonstrated to have a favorable impact on cardiovascular morbidity and mortality. Whereas each of these agents has multiple therapeutic effects, it does raise questions with regard to HDL-C raising. This is further supported by the lack of evidence from genomic studies of an association between HDL-C and CVD.
What we have learned is that HDL is highly complex, circulating in a range of forms. The relative contribution of these subspecies to atheroprotection is unknown. It is of use to note that infusing lipid-deplete forms of HDL promotes rapid regression of coronary atherosclerosis in humans, in the absence of any long-term impact on HDL-C levels (9). When combined with reports that measures of the functional activity of HDL may be superior in their ability to predict cardiovascular risk when compared with HDL-C suggests that qualitative measures of HDL may be more important in terms of atheroprotection (10) and therefore provides a shining light of hope that we may still find favorable approaches to targeting HDL to reduce cardiovascular risk. The good news is that considerable activity continues to determine whether more qualitative approaches to targeting HDL will be favorable. Let us hope that big data has the opportunity to help guide the way.
↵∗ 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 AstraZeneca, Amgen, Cerenis, Eli Lilly, InfraReDx, Novartis, Resverlogix, Roche, and Sanofi-Regeneron; and is a consultant for AstraZeneca, Amgen, Boehringer Ingelheim, CSL Behring, Cerenis, Eli Lilly, Merck, Takeda, Roche, Pfizer, Novartis, and Sanofi-Regeneron. Dr. Psaltis has reported that he has no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Libby P.
- Gordon D.J.,
- Probstfield J.L.,
- Garrison R.J.,
- et al.
- Ko D.T.,
- Alter D.A.,
- Guo H.,
- et al.