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28 July 2010
Lipid targets beyond LDL-C for predicting residual coronary risk: the EPIC*-Norfolk study

Elevated non-HDL-C levels, triglycerides =150 mg/dL and a total cholesterol/HDL-C ratio =5 are predictive of residual coronary risk beyond LDL-C, and could be considered as valuable input to risk assessment algorithms.

Arsenault BJ, Rana JS, Stroes ESG et al.
Comments & References

11-year follow-up data from 21,448 men and women aged ≥45 years without diabetes or coronary heart disease (CHD) at baseline, were included in this prospective population-based study. The relative contributions to coronary risk of non-fasting:
• non high-density lipoprotein cholesterol (non-HDL-C) ≥30 mg/dL higher than LDL-C, evocative of triglycerides (TG)-rich lipoproteins enrichment
• TG ≥150 mg/dL and
• ratio of total cholesterol (TC) to HDL-C ≥5
were analysed across each category of LDL-C (derived from the National Cholesterol Education Program Adult Treatment Panel III1). Adjustment was made for conventional cardiovascular risk factors (age, sex, smoking, systolic blood pressure, waist circumference and physical activity), as well as hormone replacement therapy in women.

Main results

Across all LDL-C categories, individuals with an elevated non HDL C (as defined above), TG ≥150 mg/dL or TC/HDL C ≥5 were at increased risk of CHD.

This was especially notable in subjects with LDL-C levels at goal (<100 mg/dL). In this group, adjusted hazard ratios for coronary risk were:
• 1.84 (95% CI 1.12-3.04) for non-HDL-C ≥130 mg/dL (vs. non-HDL-C<130 mg/dL)
• 1.63 (95% CI 1.02-2.59) for TG ≥150 mg/dL (vs. TG <150 mg/dL)
• 2.19 (95% CI 1.22-3.93) for TC/HDL-C ≥5 (vs. TC/HDL-C <5)


Current guidelines recommend LDL-C as the primary lipid target for prevention of cardiovascular disease. However, even in individuals with LDL-C levels at goal, there remains a high residual cardiovascular risk.2,3

Non-HDL-C is a measure of the combined cholesterol from all atherogenic apolipoprotein B100-containing lipoproteins and, to a lesser degree, of apolipoprotein B48-containing lipoproteins, including LDL, very low-density lipoproteins, intermediate-density lipoproteins, lipoprotein(a), chylomicrons and their remnants. Non-HDL-C is already recognised by US guidelines as a secondary target for therapy.1,4 In fact, the recent ADA/ACC Consensus statement for lipoprotein management 20085 highlights the importance of measurement of apolipoprotein B100-containing lipoproteins as a component of residual cardiovascular risk. In an accompanying editorial,6 it is proposed that the current study supports the use of non-HDL-C as a routine target of therapy to reduce cardiovascular risk.

Non-LDL lipids are predictive of residual coronary risk

The EPIC-Norfolk study clearly demonstrates that non-LDL components of the lipid-lipoprotein profile, specifically elevated TG, and by inference, low HDL-C, (presence of both abnormalities being labeled atherogenic dyslipidemia), are important contributors to residual coronary risk in individuals at LDL-C goal.

With respect to TG, coronary risk associated with TG ≥150 mg/dL was consistent with that reported from a grand meta-analysis of 29 prospective studies including 262,525 subjects. This analysis reported an odds ratio of 1.72 (95% CI 1.56-1.90) when individuals in the third log-TG tertile were compared with those in the first log-TG tertile (corresponding to mean TG values >178 mg/dL vs. <115 mg/dL). The strength of this association was maintained even after adjustment for HDL-C levels.7 Additionally, the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22) study,8 post-hoc analysis showed that statin-treated patients at LDL-C goal with elevated fasting TG (≥150 mg/dL) had a high residual coronary risk, even after adjustment for confounders, including HDL-C. As discussed,6 non-fasting TG, as measured in the current study, may even better predict residual coronary risk than fasting TG values. The authors of the EPIC-Norfolk study do, however, recognize that the lack of adjustment for HDL-C, as well as for diabetes and/or insulin resistance, may limit the strength of the observed association between TG and coronary risk.

The importance of low HDL-C as another major contributor to residual cardiovascular risk is supported by data from observational studies such as the Prospective Cardiovascular Münster (PROCAM) study,9 as well as post-hoc analysis of statin-treated patients at LDL-C goal (<70 mg/dL) with low levels of HDL-C (<37 mg/dL).10 Findings from the EPIC-Norfolk study are consistent with evidence from PROCAM in showing that in individuals with a TC/HDL-C ratio ≥5.0, coronary risk was more than 2 fold higher than in those with a ratio <5. This provides further support for the use of this ratio for coronary risk assessment beyond LDL-C, as recognised in the recently updated Canadian guidelines for management of dyslipidemia.11

Together with findings from the EPIC-Norfolk study, there is mounting evidence to support measurement of non-LDL parameters associated with the hallmark abnormalities defining atherogenic dyslipidemia – elevated TG and the TC/HDL-C ratio - for assessing residual coronary risk beyond LDL-C.

References 1. Grundy SM, Cleeman JI, Merz NB et al. Arterioscler Thromb Vasc Biol 2004;24:e149-e161.
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3. LaRosa JC, Grundy SM, Waters DD et al Treating to New Targets (TNT) Investigators. N Engl J Med 2005; 352:1425-35.
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6. Robinson JG. J Am Coll Cardiol 2010;55:42-44.
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11. Genest J, McPherson R, Frohlich J et al. Can J Cardiol 2009;25:567-79.