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Lipoprotein(a) – does it matter when LDL cholesterol is low?

Posted on 27 July 2018 | Posted by Anthony Wierzbicki | Posted in From the Editors

Lipoprotein(a) is now recognised as an independent risk factor for cardiovascualr disease. But is it also relevant to consider lipoprotein(a) when LDL cholesterol is low? Prof. Anthony S Wierzbicki, Guy’s and St Thomas’ Hospitals, London, UK discusses the evidence.

Lipoprotein(a) [Lp(a)] is a well-characterised biomarker used for baseline cardiovascular disease (CVD) risk assessment.1,2The evidence for this is now established. In the Copenhagen City Heart Study, Lp(a) was shown to be a significant independent CVD risk factor in both men and women,3and use of Lp(a) concentrations (80thcentile; 47mg/dL) allowed re-classification of CVD risk in 12% of individuals.4A meta-analysis from the Emerging Risk Factors Collaboration including 126,634 individuals from epidemiological studies showed that Lp(a) identified a relative risk for CVD of 4.4 – 5.6 between extreme tertiles.5 Additional evidence for a causal association of Lp(a) with CVD comes from genome association and Mendelian randomization studies.

The measurement of Lp(a), however, has caused some problems.1,2Currently, isotype-independent immunoassays are preferred, with levels in excess of 50 mg/dL or 125 nmol/L identifying high-risk individuals.1,2Lp(a) is found between high-density lipoprotein (HDL) and LDL species but allowances are not usually made for its presence. The commonly used Friedewald equation will underestimate LDL cholesterol in the presence of minimally elevated triglycerides,6,7but also in patients treated with highly efficacious LDL cholesterol-lowering therapies,8while LDL cholesterol is overestimated if the contribution of high Lp(a) concentrations is ignored.9,10The effects of correction for Lp(a) on diagnostic LDL cholesterol criteria (>190 mg/dL; 4.9 mmol/l) and goals (< 70mg/dl; 1.8 mmol/L) have been investigated using two methods in 531,140 patients in the Very Large Database of Lipids (VLDL) study. Correction for Lp(a) reduced the proportion of patients with high LDL cholesterol from 1.4% to 0.86% (p<0.001) and established that 23% rather than 17% were at LDL cholesterol goal (p<0.001). This discrepancy may affect the prescription of PCSK9 inhibitors as their initiation guidelines are related to LDL cholesterol concentrations.11

Historical studies suggested that Lp(a) was a weak CVD risk factor and that adequate control of LDL cholesterol negated its significance. In the Familial Atherosclerosis Treatment study (FATS) in 146 patients treated with niacin treatment combined with statins and bile acid sequestrants, while Lp(a) correlated with disease burden, only tight control of LDL cholesterol-<2.5 mmol/L (100 mg/dL) was significant in determining progression of angiographic coronary disease.12 A later analysis of LDL cholesterol control in 2769 patients presenting for coronary angiography, including 38% with Lp(a) >30mg/dL, confirmed the relationship of Lp(a) with angiographic progression of disease but found that control of LDL cholesterol to <1.8 mmol/L (80 mg/dL) negated the effects of elevated Lp(a).13Additionally, in the Dalcetrapib in Acute Coronary Syndrome Studies (Dal-Outcomes), Lp(a) was not a significant factor driving CV event rates in patients in both the placebo (n=3170) and intervention groups (n=969) receiving aggressive anti-platelet therapy and with adequately treated LDL cholesterol (<2.5 mmol/L).14  Most recently, analysis of the EPIC cohort has shown that elevated Lp(a) (>80thcentile) is not a significant contributor to CVD risk in primary prevention if LDL cholesterol is controlled to <2.5 mmol/L.15 Thus, current evidence suggests that if LDL cholesterol is adequately controlled then Lp(a) is not a factor in driving progression of disease.

Some novel lipid-lowering therapies reduce Lp(a).  PCSK9 inhibitors reduce Lp(a) by 18-32%.16Data from the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) study confirmed that Lp(a) levels were associated with higher rates of events. Treatment with evolocumab reduced Lp(a) levels by 25%, and resulted in greater relative (reduction of 24% in patients with high Lp(a) vs. 15% in those with low Lp(a)) and absolute reductions (2.8% versus 1.3%) in CVD events.17

So, what are the take home messages for clinicians regarding the relevance of Lp(a)? It is clear – and recommended by current guidelines – that Lp(a) can be used to define individuals at high CVD risk. Additionally, with evidence that intervention with a PCSK9 inhibitor reduces CVD events in patients with high Lp(a), the presence of a high Lp(a) level may be a useful additional factor in determining the need for PCSK9 inhibitor therapy.

References

  1. Nordestgaard BG, Chapman MJ, Ray K et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010; 31: 2844-53. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/20965889
  2. Kostner KM, Kostner GM, Wierzbicki AS. Is Lp(a) ready for prime time use in the clinic? A pros-and-cons debate. Atherosclerosis 2018; 274: 16-22. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/29747086
  3. Kamstrup PR, Benn M, Tybaerg-Hansen A, Nordestgaard BG. Extreme lipoprotein(a) levels and risk of myocardial infarction in the general population: the Copenhagen City Heart Study. Circulation 2008; 117: 176-84. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/18086931
  4. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 2009; 301: 2331-9. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/19509380
  5. Emerging Risk Factors C, Erqou S, Kaptoge S et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009; 302: 412-23. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/19622820
  6. Martin SS, Blaha MJ, Elshazly MB et al. Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications. J Am Coll Cardiol 2013; 62: 732-9. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/23524048
  7. Martin SS, Blaha MJ, Elshazly MB et al. Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile. JAMA 2013; 310: 2061-8. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/24240933
  8. HPS TIMI REVEAL Collaborative Group, Bowman L, Hopewell JC et al. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med 2017; 377: 1217-27. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/28847206
  9. Yeang C, Witztum JL, Tsimikas S. 'LDL-C' = LDL-C + Lp(a)-C: implications of achieved ultra-low LDL-C levels in the proprotein convertase subtilisin/kexin type 9 era of potent LDL-C lowering. Curr Opin Lipidol 2015; 26: 169-78. PUBMEDhttps://www.ncbi.nlm.nih.gov/pubmed/25943842
  10. Li KM, Wilcken DE, Dudman NP. Effect of serum lipoprotein(a) on estimation of low-density lipoprotein cholesterol by the Friedewald formula. Clin Chem 1994; 40: 571-3. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/8149612
  11. Viney NJ, Yeang C, Yang X et al. Relationship between "LDL-C", estimated true LDL-C, apolipoprotein B-100, and PCSK9 levels following lipoprotein(a) lowering with an antisense oligonucleotide. J Clin Lipidol 2018;12:702-10. PUBMEDhttps://www.ncbi.nlm.nih.gov/pubmed/29574075
  12. Maher VM, Brown BG, Marcovina SM et al. Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a). JAMA 1995; 274: 1771-4. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/7500507
  13. Nicholls 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: 3055-61. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/20601648
  14. Schwartz GG, Ballantyne CM, Barter PJ et al. Association of lipoprotein(a) with risk of recurrent ischemic events following acute coronary syndrome: analysis of the dal-Outcomes randomized clinical trial. JAMA Cardiol 2018; 3: 164-8. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/29071331
  15. 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 prevention setting. Eur Heart J 2018; 39: 2589-96. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/29931232
  16. Enkhmaa B, Anuurad E, Zhang W et al. The roles of apo(a) size, phenotype, and dominance pattern in PCSK9-inhibition-induced reduction in Lp(a) with alirocumab. J Lipid Res 2017; 58: 2008-16. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/28798072
  17. PCSK9 Forum. 2018 10.05.2018. FOURIER looks at impact of baseline lipoprotein(a). [cited 2018 23/07]; Available from https://www.pcsk9forum.org/fourier-looks-impact-baseline-lipoproteina/

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