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Macrovascular Residual Risk THROUGH LANDMARK STUDY

13 April 2015
Elevated nonfasting remnant cholesterol associated with increased mortality

Results from an analysis of 90,000 Danish individuals showed that increased nonfasting remnant cholesterol and increased low-density lipoprotein cholesterol (LDL-C) are associated equally with the risk of ischaemic heart disease and myocardial infarction. However, only nonfasting remnant cholesterol concentration was associated with increased all-cause mortality.

Varbo A, Freiberg J, Nordestgaard B.
Extreme nonfasting remnant cholesterol vs extreme LDL cholesterol as contributors to cardiovascular disease and all-cause mortality in 90,000 individuals from the general population.
Clin Chem 2015;61:533-543.
Summary
Comments & References
STUDY SUMMARY
Objective: To evaluate whether nonfasting remnant cholesterol and LDL-C are equal contributors to the risk of ischaemic heart disease [IHD], myocardial infarction [MI] and all-cause mortality.
Study design: Analysis of data from two prospective studies – the Copenhagen City Heart Study (CCHS) (n=9,558) and the Copenhagen General Population Study (CGPS) (n=88,404). Participants were followed prospectively for up to 22 years.
Study population: Both studies included participants from the general population in Denmark; the CCHS was initiated in 1976–78, and the CGPS was initiated in 2003. LDL-C was distributed normally and nonfasting remnant cholesterol was skewed with a tail toward higher concentrations.
Methods: Participants were divided into clinically meaningful groups with increasing concentrations of nonfasting remnant cholesterol (<0.5, 0.5–0.99, 1–1.49 and ≥1.50 mmol/L) and LDL-C (<3, 3–3.99, 4–4.99 and≥5 mmol/L); similar proportions of subjects were included in the top groups to allow direct comparison of extremely high concentrations of each parameter with respect to risk of IHD, MI and all-cause mortality. Information on IHD and MI diagnoses were obtained by reviewing all hospital admissions and diagnoses in the Danish Patient Registry and all causes of death entered in the national Danish Causes of Death Registry.  Cox proportional hazard regression models were used to estimate hazard ratios.
Main results: • During up to 22 years of complete follow-up, 4,435 subjects developed IHD, 1722 developed MI, and 8121 died.
• When subjects with nonfasting remnant cholesterol concentration <0.5 mmol/L were used as the comparison group, multivariable adjusted hazard ratios for IHD ranged from 1.3 (95% CI 1.1–1.5) for a remnant cholesterol concentration of 0.5–0.99 mmol/L to 2.4 (1.9 –2.9) for remnant cholesterol ≥1.5 mmol/L (P for trend <0.001).
• When subjects with LDL-C <3.0 mmol/L were used as the comparison group, hazard ratios for IHD ranged from 1.3 (1.1–1.5) for a LDL-C concentration of 3–3.99 mmol/L to 2.3 (1.9 –2.8) for LDL-C ≥5 mmol/L (P<0.001).
• Corresponding hazard ratios for MI ranged from 1.8 (1.4 –2.3) to 3.4 (2.5– 4.8) for remnant cholesterol (P<0.001), and from 1.7 (1.4 –2.2) to 4.7 (3.5– 6.3) for LDL-C (P<0.001).
• Nonfasting remnant cholesterol concentrations were associated stepwise with all-cause mortality ranging from hazard ratio 1.0 (0.9 –1.1) to 1.6 (1.4 –1.9) (P<0.001). In contrast, LDL-C concentrations were associated with decreased risk of all-cause mortality in a U-shaped pattern, with hazard ratios from 0.8 (0.7– 0.8) to 0.9 (0.8 –1.0) (P=0.002)
Authors’ conclusion: Both lipoproteins were associated equally with risk of IHD and MI; however, only nonfasting remnant cholesterol concentrations were associated stepwise with increased all-cause mortality risk.

COMMENT

Remnant cholesterol, defined as total cholesterol – LDL-C – high-density lipoprotein cholesterol, is the cholesterol content of the triglyceride-rich lipoproteins composed of very low-density lipoproteins and intermediate density lipoprotein in the fasting state, and both of these lipoproteins together with chylomicron remnants in the nonfasting state. Remnant cholesterol concentrations are consequently highly correlated with triglycerides.

 There is a growing evidence-base that remnant lipoproteins are atherogenic.1 Previous reports have highlighted that lifelong exposure to elevated remnant cholesterol levels (by carriage of genetic variants associated with triglyceride metabolism) translates to a 2-fold greater risk of ischaemic heart disease, compared with that reported for observational data.2 These findings clearly implicate remnant cholesterol as causal for cardiovascular disease. Given that remnants are known to cross the endothelial barrier,3 it is likely that the response to lipid retention hypothesis explains their atherogenicity. Moreover, because of their larger size, remnant lipoproteins contain much cholesterol per particle than LDL, and this may result in increased cardiovascular risk.

 This study adds to evidence by indicating that remnant cholesterol is an important contributor to residual cardiovascular risk. Whereas the risk of IHD and MI increased similarly for stepwise increasing nonfasting remnant and LDL-C concentrations, only nonfasting remnant cholesterol was associated with increased all-cause mortality risk. One point to consider is the definition of remnant cholesterol. Varbo and colleagues calculated this as non-fasting triglycerides divided by 5, which would therefore encompass more than the cholesterol of "remnant" particles, as it measures non-fasting triglyceride-rich lipoprotein-cholesterol. This issue will be discussed in a future post.

 Despite this consideration, the totality of available evidence argues for renewed focus on therapeutic intervention aimed at lowering remnant cholesterol to reduce the high residual cardiovascular risk that persists despite best-evidence based treatment including statins.

References

1. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626-35.

2. Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427-36.

3. Mamo JC, Proctor SD, Smith D. Retention of chylomicron remnants by arterial tissue; importance of an efficient clearance mechanism from plasma. Atherosclerosis 1998;141:S63-S69.

Key words   LDL cholesterol, nonfasting remnant cholesterol, cardiovascular risk