Commentary on Triglyceride-rich lipoproteins and HDL

Triglyceride-rich lipoproteins and HDL: what do recent trials tell us?

Cardiometabolic disease is the leading, preventable cause of death worldwide. Elevated triglycerides, a marker of triglyceride-rich lipoproteins (TRL), with or without low plasma concentration of high-density lipoprotein (HDL) cholesterol, is a key driver of atherogenic risk associated with cardiometabolic disease. The European Atherosclerosis Society (EAS) Consensus Panel has highlighted this association in a recent position paper.1 However, in the light of recent developments there has been confusion about the relevance of each factor to this increased cardiovascular risk.

HDL Controversy

Undoubtedly, a low plasma concentration of HDL cholesterol is a cardiovascular risk factor, robustly supported by population data from the Emerging Risk Factors Collaboration.2 On this basis, HDL cholesterol is now included as a cardiovascular risk factor in SCORE.3 Yet in recent trials, therapeutic intervention aimed at targeting HDL cholesterol to reduce cardiovascular risk failed to show benefit. AIM-HIGH,4 which specifically targeted a high-risk statin-treated population with low HDL cholesterol, was criticised for methodological and statistical issues. More pessimism was to follow from dal-OUTCOMES,5 which investigated the cholesteryl ester transfer protein inhibitor dalcetrapib in an acute coronary syndrome (ACS) population. Dalcetrapib has negligible effects on apolipoprotein B-containing lipoproteins, and therefore offered perhaps the best opportunity to date to test the HDL hypothesis. However, it has been suggested that this population may have been less than ideal, given in vitro evidence that the biological activity of HDL particles may have been compromised in the inflammatory conditions associated with ACS.6

Most recently, topline results from HPS2-THRIVE7 failed to show any benefit with niacin/laropiprant in a broader patient population. There were also safety issues, with a significant increase in the incidence of some types of non-fatal serious adverse events in the group that received this combination treatment, which prompted the world—wide withdrawal of this product. In the absence of the full study data it has been speculated that these findings might relate to the effects of laropiprant, although it is not possible to definitively discern this, with the lack of niacin and laropiprant monotherapy comparator arms. Furthermore, niacin is known to have a broad spectrum of lipid-modifying activity, including LDL cholesterol, triglycerides and lipoprotein(a). On the plus side, it is acknowledged that niacin has been in clinical use for over 50 years and has a well characterised adverse effect profile. In contrast, there is limited experience with laropiprant. We await the full report of this study in the coming month.

One line of argument to explain the HDL controversy is that HDL concentration is a poor metric for targeted intervention. HDL cholesterol concentration is considered a surrogate for the efficiency of cholesterol efflux from tissues. However, given that macrophage-derived cholesterol represents only a minor proportion of the cholesterol transported by HDL particles, this may be an inadequate measure. Moreover, HDL cholesterol concentration is a static measurement, and does not take into account the dynamics of HDL particle population and its functionality. Thus, HDL function may be a preferable measure. However, which is the best index of HDL functionality? And how do we translate this measure to the clinical setting? Currently, measurement of HDL functionality is a research tool and much remains to be done to validate it.

The HDL quality versus quantity debate continues…

Remnant cholesterol: Causal for heart disease

In contrast, a recent study8 has helped to clarify the role of TRL as a driver of atherogenic risk in non-fasting individuals. Remnant cholesterol is the cholesterol carried by TRL remnants, and in this study was calculated as non-fasting total cholesterol minus LDL cholesterol minus HDL cholesterol. Previous studies have indicated that elevated plasma levels of remnant cholesterol are associated with endothelial dysfunction, a marker for atherosclerotic disease. Remnants are also known to cross the endothelial barrier of the arterial wall. Additionally, there is evidence from observational studies that elevated levels of remnant cholesterol are associated with increased cardiovascular risk, although confounding due to other risk factors and metabolic interrelationships with HDL did not permit investigation of causality.

The current study aimed to obviate this confounding by using a Mendelian randomisation approach, which can be considered a ‘natural’ randomised trial. This strategy takes advantage of the “randomisation” of genetic information at birth to evaluate a potential causal relationship between a genetically determined biomarker and an outcome.

In this study, investigators tested the causal effect of lifelong exposure to elevated remnant cholesterol concentration on risk for coronary disease, based on data from three major Danish studies (two in the general population and one in individuals with ischaemic heart disease). A total of 73,513 subjects (11,984 with ischaemic heart disease) were genotyped for 15 genetic variants affecting levels of remnant cholesterol alone; both remnant cholesterol and HDL cholesterol; HDL cholesterol alone or LDL cholesterol alone (positive control).

In summary, the investigators showed that remnant cholesterol concentration was a causal risk factor for ischaemic heart disease. A 1 mmol/L (39 mg/dL) increase in non-fasting remnant cholesterol was associated with a 2.8-fold causal risk for ischaemic heart disease, higher than for observational data alone (hazard ratio 1.4, 95% CI: 1.3 to 1.5). The association was independent of HDL cholesterol concentration. In further support, genome wide association studies show concordance between the increase in coronary risk associated with genetic variants influencing TRL pathways and observational studies.9 Instead, studies of genetic variants influencing HDL concentration failed to show a causal association between genetically raised plasma HDL cholesterol levels and risk for myocardial infarction, in contrast to observational data.10

Key Questions

  • Does the failure of recent clinical studies for interventions targeting HDL cholesterol reflect the fact that HDL cholesterol concentration is a poor surrogate for HDL function?
  • Do the data from the study by Varbo and colleagues support routine measurement of remnant lipoprotein cholesterol?

Lipoprotein(a) and valvular calcification

An important new study adds to the evidence-base for lipoprotein(a) as a cardiovascular risk factor, previously highlighted by the EAS Consensus Panel statement.11 This study investigated genome-wide associations with valvular calcification, an important precursor of clinical valve disease, in over 10,000 subjects participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.12 The presence of valve calcification was confirmed by computed tomographic (CT) scanning.

In the first part of the study, investigators evaluated 2.5 million single nucleotide variants in 6,942 subjects with aortic valve calcification. They identified a variant in the Lp(a) locus—rs10455872—that reached genome-wide significance for the presence of aortic-valve calcification on CT scan (odds ratio per allele 2.05; p=9×10-10). This finding was replicated in an additional 2000 people of Hispanic origin, about 2500 African Americans, and more than 700 Germans (p<0.05 for all comparisons). Using a Mendelian randomisation approach, the investigators showed that for genetically determined Lp(a) levels, each log unit increase in Lp(a) concentration was associated with ∼62% increase in the odds of aortic-valve calcification. Subsequent investigation in a Swedish cohort (from the Malmö Diet and Cancer Study) showed that this Lp(a) variant was associated with incident aortic stenosis (HR per allele, 1.68; 95% CI 1.32 to 2.15) and aortic-valve replacement (HR ratio, 1.54; 95% CI 1.05 to 2.27). The association with incident aortic stenosis was replicated in a Danish cohort from the Copenhagen City Heart Study. Together these data implicate Lp(a) in the development of valvular calcification in later life.

In conclusion, the current study extends the current evidence-base for Lp(a) and indicates a common role for this risk factor in the pathogenesis of atherosclerosis and calcified aortic valve disease. Lp(a) is not only predictive for increased risk for myocardial infarction, as highlighted in the EAS Consensus Panel statement,11 but also for increased risk for aortic stenosis. Together, these findings make a strong case for investigation of potential therapeutic strategies for managing elevated Lp(a).

Key Points

  • In this study, a genetic variant of Lp(a) – rs10455872- was strongly associated with aortic-valve calcification, a precursor to aortic valve disease.
  • People carrying this variant had about a 2-fold increase in the risk of valve calcification as assessed by CT scan, compared with those without this allele.
  • These data extend the evidence-base for Lp(a) and make the case for investigation of potential therapeutic approaches for targeting this risk factor.


  1. Chapman MJ, Ginsberg HN, Amarenco P, et al; European Atherosclerosis Society Consensus Panel. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61.
  2. Emerging Risk Factors Collaboration, Di Angelantonio E, Sarwar N, Perry P et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993-2000.
  3. Catapano AL, Reiner Z, De Backer G et al. ESC/EAS Guidelines for the management of dyslipidaemias. The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis 2011;217:3-46.
  4. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67.
  5. Schwartz GG, Olsson AG, Abt M et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089-99.
  6. Camont L, Chapman MJ, Kontush A. Biological activities of HDL subpopulations and their relevance to cardiovascular disease. Trends Mol Med. 2011;17:594-603.
  7. Merck Announces HPS2-THRIVE Study of TREDAPTIVE™ (Extended-Release Niacin/Laropiprant) Did Not Achieve Primary Endpoint. Available from:, December 20, 2012.
  8. Varbo A, Benn M, Tybjærg-Hansen A et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427–36.
  9. Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration, Sarwar N, Sandhu MS, Ricketts SL et al. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet 2010;375:1634-9.
  10. Voight BF, Peloso GM, Orho-Melander M et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012;380:572-80.
  11. Nordestgaard BG, Chapman MJ, Ray K et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844-53.
  12. Thanassoulis G, Campbell CY, Owens DS et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med 2013;368:503-12.