What role for lipoprotein(a) in clinical practice?
Authors: Stephen J Nicholls, Peter J Psaltis
Journal: The Lancet Diabetes & Endocrinology (2017)

For more than two decades, the role of cholesterol lowering in the prevention of atherosclerotic cardiovascular disease has been increasingly established. Research findings have shown that reduction of LDL cholesterol can favourably modulate atherosclerotic plaque and reduce the risk of cardiovascular events.1Nicholls SJ Ballantyne CM Barter PJ et al.Effect of two intensive statin regimens on progression of coronary disease.N Engl J Med. 2011; 365: 2078-2087Crossref PubMed Scopus (622) Google Scholar, 2Cholesterol Treatment Trialists' (CTT) CollaborationEfficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials.Lancet. 2010; 376: 1670-1681Summary Full Text Full Text PDF PubMed Scopus (4517) Google Scholar As findings from studies have continued to show the incremental benefits of more intensive lipid lowering, treatment guidelines for cardiovascular prevention have promoted the use of more potent statin therapy for patients deemed to be at high risk of cardiovascular disease. The development of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors provides the potential to lower cholesterol even further, with early reports of cardiovascular benefit with evolocumab in the FOURIER CV outcomes trial.3AmgenAmgen announces Repatha® (Evolocumab) significantly reduced the risk of cardiovascular events in FOURIER outcomes study.http://www.amgen.com/media/news-releases/2017/02/amgen-announces-repatha-evolocumab-significantly-reduced-the-risk-of-cardiovascular-events-in-fourier-outcomes-study/Date: Feb 2, 2017Google Scholar Accordingly, there is considerable hope in the clinical community that we might be able to lower cardiovascular risk more effectively in a greater proportion of our patients than with current standard of care. However, despite these advances, the sobering reality indicates that many patients who are given these treatments will continue to have progressive disease and cardiovascular risk. This residual risk has fuelled the search to identify additional modifiable targets that will enable further cardiovascular risk reduction. One such factor that continues to receive widespread interest is lipoprotein(a). Traditionally taught in medical schools as an obscure factor investigated in young patients (younger than 40 years) with myocardial infarction who have no discernible risk factors, lipoprotein(a) has emerged as a new potential target for cardiovascular risk reduction. The substantial interest in lipoprotein(a) is based on studies that have elucidated both its molecular biochemistry and its vascular biological effects. Results from cohort studies have shown an association between lipoprotein(a) concentration and cardiovascular risk,4The Emerging Risk Factors CollaborationLipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality.JAMA. 2009; 302: 412-423Crossref PubMed Scopus (1961) Google Scholar and findings from genomic studies have conclusively established a causative role for lipoprotein(a) in atherosclerotic cardiovascular disease.5Kamstrup PR Tybjaerg-Hansen A Steffensen R Nordestgaard BG Genetically elevated lipoprotein(a) and increased risk of myocardial infarction.JAMA. 2009; 301: 2331-2339Crossref PubMed Scopus (848) Google Scholar In The Lancet Diabetes & Endocrinology, Danish Saleheen and colleagues6Saleheen D Haycock PC Zhao W et al.Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis.Lancet Diabetes Endocrinol. 2017; (published online April 10.)http://dx.doi.org/10.1016/S2213-8587(17)30088-8Summary Full Text Full Text PDF PubMed Scopus (130) Google Scholar extend the genetic observations relating lipoprotein(a) and cardiovascular risk. Using genomic analysis of more than 190 000 individuals, including nearly 70 000 with established coronary heart disease, Saleheen and colleagues systematically investigated the association between genetic variants that affect both lipoprotein(a) concentration and isoform size with cardiovascular events. The investigators report that clinical events were independently associated with high concentrations of lipoprotein(a) (odds ratio [OR] 1·10 [95% CI 1·05–1·14; p<0·0001] per 1-SD increment in lipoprotein(a) concentration) and smaller apolipoprotein(a) isoforms (OR 0·93 [0·90–0·97; p<0·0001] per 1-SD increment in LPA KIV2 repeats). The derivation of these findings from a large, systematic, genetic analysis provides strong evidence implicating lipoprotein(a) as a causal factor in atherosclerosis. The logical question extending from all of these findings is how can lipoprotein(a) be integrated into clinical practice? Has lipoprotein(a) evolved to become an important clinical factor, beyond investigation of patients whose coronary disease cannot be explained by conventional risk factors? The answer to this question would appear to be a resounding yes. The challenge lies in defining what the extended activity should look like. Should all patients be screened for lipoprotein(a) concentration in risk assessment? In patients at highest risk of cardiovascular disease, would such screening make a difference, given that these patients are already given intensive statin therapy? The presence of a raised lipoprotein(a) concentration has been shown to increase the high cardiovascular risk in patients with familial hypercholesterolaemia,7Chan DC Pang J Hooper AJ et al.Elevated lipoprotein(a), hypertension and renal insufficiency as predictors of coronary artery disease in patients with genetically confirmed heterozygous familial hypercholesterolemia.Int J Cardiol. 2015; 201: 633-638Summary Full Text Full Text PDF PubMed Scopus (60) Google Scholar and other reports have suggested that lipoprotein(a)-associated risk is attenuated in patients with low LDL cholesterol concentrations.8Nicholls SJ Tang WH Scoffone H et al.Lipoprotein(a) levels and long-term cardiovascular risk in the contemporary era of statin therapy.J Lipid Res. 2010; 51: 3055-3061Crossref PubMed Scopus (69) Google Scholar Would such measurements influence clinical practice, where clinicians are reluctant to use high dose statins, despite their recommendation in treatment guidelines? Because these findings are all derived from observational studies, surely the time has come to test the clinical and economic implications of lipoprotein(a) analysis in patients in randomised trials. The next step would then be to determine how to determine the clinical implications of lipoprotein(a) measurement over time. In view of the large genetic effect on circulating lipoprotein(a) concentrations, in the absence of an approved therapeutic intervention that lowers lipoprotein(a), serial monitoring might be of little use. Although therapies that lower lipoprotein(a) levels exist, including niacin and oestrogen, these interventions have not been shown to reduce cardiovascular risk in modern clinical trials.9HPS2-THRIVE Collaborative GroupEffects of extended-release niacin with laropiprant in high-risk patients.N Engl J Med. 2014; 371: 203-212Crossref PubMed Scopus (1161) Google Scholar PCSK9 inhibitors lower lipoprotein(a) concentration, but it will be difficult to dissect any potential contribution of this effect on clinical outcomes from their robust reduction of LDL cholesterol. Cholesteryl ester transfer protein inhibitors also reduce lipoprotein(a) concentrations, but three such inhibitors have not showed a clinical benefit,10Barter PJ Caulfield M Eriksson M et al.Effects of torcetrapib in patients at high risk for coronary events.N Engl J Med. 2007; 357: 2109-2122Crossref PubMed Scopus (2601) Google Scholar despite a range of favourable lipoprotein effects. Specific lipoprotein(a)-targeted drugs have been developed and are being assessed at present.11Viney NJ van Capelleveen JC Geary RS et al.Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials.Lancet. 2016; 388: 2239-2253Summary Full Text Full Text PDF PubMed Scopus (461) Google Scholar Whether these drug candidates can be used in broad patient cohorts or will require validation in patients with increased lipoprotein(a) concentration remains to be determined. Accordingly, considerable work continues to define the optimum role of lipoprotein(a) in clinical practice. All of this research activity would suggest that lipoprotein(a) has become a major target in the reduction of cardiovascular disease risk. Whether lipoprotein(a) will become a pivotal factor in our search to achieve incremental risk reduction in a broad cohort of patients or remains a niche factor limited to management of young patients at high risk of premature cardiovascular disease is uncertain. In an era in which clinical practice is informed by evidence-based medicine, now is the time for lipoprotein(a) to define its clinical use. SJN has received research grants from AstraZeneca, Amgen, Eli Lilly, Cerenis, InfraReDx, Novartis, Resverlogix, The Medicines Company, and Sanofi-Regeneron, and personal fees from AstraZeneca, Amgen, Boehringer Ingelheim, CSL Behring, Eli Lilly, Kowa, Novartis, Merck, Takeda, Pfizer, Roche, and Sanofi-Regeneron, unrelated to the present work. PJP declares no competing interests. Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysisHuman genetic data suggest that both smaller apolipoprotein(a) isoform size and increased lipoprotein(a) concentration are independent and causal risk factors for coronary heart disease. Lipoprotein(a)-lowering interventions could be preferentially effective in reducing the risk of coronary heart disease in individuals with smaller apolipoprotein(a) isoforms. Full-Text PDF Open Access