Lipoprotein(a) [Lp(a)] has long been a contentious lipoprotein since its discovery 50 years ago.(1) Structurally, this lipoprotein consists of a low-density lipoprotein (LDL) particle with a glycoprotein, apolipoprotein(a), covalently linked to the apolipoprotein B100 (apoB) moiety of LDL. While earlier studies were negative,(2) recent seminal reports have unequivocally established Lp(a) as a causal and independent risk factor for cardiovascular (CV) disease, as highlighted by recent consensus.(3) As statins have limited or negligible effect on Lp(a),(4) it is therefore plausible that Lp(a) may be relevant to lipid-related residual CV risk.
Indeed, recent evidence is consistent with this. This was shown for statin-treated patients at low CV risk in the JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) group,(5) discussed in this month’s Focus on article, as well those at high CV risk, in the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/ High Triglyceride and Impact on Global Health Outcomes) study.(6) In both studies, CV risk due to Lp(a) was independent of LDL cholesterol. Thus, current evidence adds Lp(a) to triglyceride-rich lipoproteins and their remnants, as important components of lipid-related residual CV risk. The question is how best to measure these contributors to residual CV risk in clinical practice?
The Residual Risk Reduction Initiative (R3i) recently published an updated Position Paper on Residual Cardiovascular Risk.(7) In this, the R3i make the case for the use of non-high-density lipoprotein cholesterol (non-HDL-C) as a simple, practical tool to aid treatment decisions relating to the management of lipid-related residual CV risk. This recommendation is broadly consistent with the view taken by the International Atherosclerosis Society.(8)
Non-HDL-C, defined as total cholesterol - high-density lipoprotein (HDL) cholesterol, captures atherogenic cholesterol in all lipoproteins, including LDL cholesterol, triglyceride-rich apoB-containing lipoproteins (such as very low-density lipoproteins, VLDL) and their remnants, and Lp(a). In individuals with elevated triglycerides, as in atherogenic dyslipidaemia, there is an increase in VLDL-cholesterol. Therefore, in statin-treated individuals achieving LDL cholesterol targets but with persistently elevated triglycerides, especially those with insulin resistant conditions, non-HDL-C may be the best means of assessing and managing residual CV risk.
The R3i also recognises that there are practical advantages associated with the use of non-HDL-C. First, non-HDL-C does not require collection of a fasting sample. Second, non-HDL-C is easily calculated from robust lipid measures that are routinely reported by most laboratories. Third, the use of non-HDL-C avoids the issue of underestimation of risk, as is the case for calculated LDL cholesterol using the Friedewald equation in individuals with high triglycerides. Recent observations indicate that this is also relevant when patients have markedly elevated Lp(a) (>100 mg/dL).9 As laboratory facilities may differ in different regions, these are clearly important advantages to the practising clinician.
As highlighted in the R3i position paper, questions remain as to which is the best approach to managing residual CV risk. The R3i acknowledges that none of the available options (i.e. ezetimibe, fibrates or niacin) have shown outcomes benefits over statin monotherapy in major prospective trials. Clearly, new therapeutic options are needed. Of the agents in development, monoclonal antibody therapies targeting proprotein convertase subtilisin/kexin type (9) (PCSK9) have generated much interest, not only because they provide substantial reduction in LDL cholesterol on top of statin therapy, but also because these agents have other lipid-modifying effects, including reduction in Lp(a) by 25-30%.(10) These novel treatments may therefore fulfil an important role for the future in managing not only LDL cholesterol but also lipid-related residual CV risk.
1. Berg K, Mohr J. Genetics of the Lp(a) system. Acta Genet 1963;13:349-60.
2. Ridker PM, Hennekens CH, Stampfer MJ. A prospective study of lipoprotein(a) and the risk of myocardial infarction. JAMA 1993;270:2195-9.
3. Nordestgaard BG, Chapman MJ, Ray K et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844-53.
4. Kostner GM, Gavish D, Leopold B, et al. HMG CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels. Circulation 1989;80:1313-9.
5. Khera AV, Everett BM, Caulfield MP, Hantash FM, Wohlgemuth J, Ridker PM, Mora S. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin).Circulation 2014;129:635-42.
6. Albers JJ, Slee A, O’Brien KD, Robinson JG, Kashyap ML, Kwiterovich PO Jr, Xu P, Marcovina SM. Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/ High Triglyceride and Impact on Global Health Outcomes). J Am Coll Cardiol. 2013;62:1575–9.
7. Fruchart JC1, Davignon J, Hermans MP et al; Residual Risk Reduction Initiative (R3i). Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26. doi: 10.1186/1475-2840-13-26. Full article available here: http://www.cardiab.com/content/13/1/26
8. International Atherosclerosis Society. An International Atherosclerosis Society Position Paper: Global Recommendations for the Management of Dyslipidemia. Full report. Available at: http://www.athero.org/download/IASPPGuidelines_FullReport_20131011.pdf
9. Thompson GR, Seed M. Lipoprotein(a): the underestimated cardiovascular risk factor. Heart 2013’ doi: 10.1136/heartjnl-2013-304902. [Epub ahead of print].
10. Raal FJ, Giugliano RP, Sabatine MS et al. Reduction in lipoprotein (a) with the PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of over 1300 patients in 4 phase 2 trials. J Am Coll Cardiol 2014. pii: S0735-1097(14)00281-2. doi: 10.1016/j.jacc.2014.01.006. [Epub ahead of print]