Elevated remnant cholesterol: a contributor to residual mortality risk in high-risk patients

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15 March 2016

Increased remnant cholesterol but not low-density lipoprotein (LDL) cholesterol increased all-cause mortality in subjects with ischaemic heart disease.

Jepsen A-MK, Langsted A, Varbo A, Bang LE, Kamstrup PR, Nordestgaard BG. Increased remnant cholesterol explains part of residual risk of all-cause mortality in 5414 patients with ischemic heart disease. Clin Chem 2016 [Epub ahead of print]

STUDY SUMMARY

Objective:

To investigate whether increased remnant cholesterol is a risk factor for all-cause mortality in patients with ischaemic heart disease

Study design:

The Copenhagen Ischaemic Heart Disease study is a large, prospective cohort study of Danish individuals with ischaemic heart disease. The median follow-up was 7 years (range 0–12 years).

Study population:

5414 Danish patients (69% male) with ischaemic heart disease; over 50% were on a statin at baseline.

Key outcomes:

· All-cause death, as entered in the national Danish Causes of Death Registry

· Nonfasting remnant cholesterol, calculated as nonfasting total cholesterol - measured high-density lipoprotein [HDL] cholesterol - measured LDL cholesterol; and measured as the cholesterol content in chylomicron and very low-density lipoprotein (VLDL)

· Direct measured LDL cholesterol

Methods:

Patients were divided into tertiles on the basis of calculated remnant cholesterol, measured remnant cholesterol, and measured LDL cholesterol. Cox proportional hazard ratios were used to investigate the association between each lipid measure and risk for all-cause death. Multivariable adjustment was made for age, sex, smoking, hypertension, and statin use, or additionally for body mass index and diabetes.

Main results:

During 35,836 person-years of follow-up, 1319 patients died, 42% due to cardiovascular causes.

Key results are summarised.

The risk of all-cause mortality increased with higher remnant cholesterol concentrations, but not with higher concentrations of LDL cholesterol (Table 1).
Cumulative survival was 30% lower in patients with elevated calculated remnant cholesterol (≥1 mmol/L or 39 mg/dL, 27% of the cohort) compared with those with lower values (hazard ratio, 95% CI: 1.3, 1.2–1.5, p=9 x 10-6
Cumulative survival was not, however, affected by higher LDL cholesterol (≥3 mmol/L or 116 mg/dL) compared with those with lower values (hazard ratio, 95% CI: 1.0, 0.9 –1.1, p=0.76).
As 27% of patients had calculated remnant cholesterol ≥ 1 mmol/L, the population-attributable risk of all-cause mortality for calculated remnant cholesterol was 8% and 18% for uncorrected and regression dilution bias– corrected hazard ratios. Thus, these data suggest that increased concentrations of remnant cholesterol explain 8%–18% of residual risk of all-cause mortality in patients with ischemic heart disease.

Table 1. Effect of increasing remnant cholesterol or LDL cholesterol concentrations on risk for all-cause death in patients with ischaemic heart disease

Lipid parameter	Percentile	Hazard ratio (95% CI) vs. reference^a
Calculated remnant cholesterol	61-80^th 81-90^th 91-95^th 96-100^th	1.2 (1.1–1.4) 1.3 (1.1–1.5) 1.5 (1.1–1.8) 1.6 (1.2–2.0), trend, p<0.001
Measured remnant cholesterol	61-80^th 81-90^th 91-95^th 96-100^th	1.0 (0.8 –1.1) 1.2 (1.0 –1.4) 1.1 (0.9–1.5) 1.3 (1.1–1.7), trend, p=0.006
Measured LDL cholesterol	61-80^th 81-90^th 91-95^th 96-100^th	1.0 (0.9 –1.1) 1.0 (0.8 –1.2) 1.0 (0.8 –1.3) 1.1 (0.8 –1.4). trend p=0.88

^a reference group was patients with values in 0-60^th percentiles

Authors’ conclusion:

These data suggest that increased concentrations of remnant cholesterol explain part of the residual risk of all-cause mortality in patients with ischaemic heart disease.

COMMENT

Accumulating evidence shows that elevated remnant cholesterol, the cholesterol contained in triglyceride-rich lipoproteins, is causally associated with an increased risk for ischaemic heart disease (1). The results of this study add to this, by showing that elevated remnant cholesterol is also associated with an increased risk for all-cause mortality in individuals with ischaemic heart disease. In contrast, there was no association between LDL cholesterol and all-cause mortality in this patient group. The large patient cohort with no loss to follow-up, together with the use of all-cause mortality as the definitive hard clinical outcome add to the strength of these findings. Moreover, even though patients were categorised on the basis of single measurements of remnant cholesterol and LDL cholesterol, given the variability of remnant and LDL cholesterol concentrations, this would be expected to lead to regression dilution bias, and therefore the results should be regarded as minimal estimates of risk.

Mechanistic studies have shown that remnant particles, like LDL particles, are able to penetrate and be retained within the arterial wall, and consequently play a role in initiation of the inflammatory atherosclerotic process (2,3). Even in individuals with well controlled LDL cholesterol levels, elevated triglycerides (a marker of elevated remnant cholesterol) contribute to lipid-related residual cardiovascular risk. Additionally, and as shown by this report, elevated remnant cholesterol also appears to be associated with low-grade inflammation (4), thus contributing to residual cardiovascular risk via non-lipid pathways.

From the clinical perspective, the findings of this and other studies, make the case for consideration of remnant cholesterol as a therapeutic target for reducing this residual risk. Even with the advent of novel agents that are effective in lowering LDL cholesterol to much lower levels, management of elevated remnant cholesterol continues to be problematic. Novel therapies effective against this target are clearly needed to address the unresolved issue of lipid-related residual cardiovascular risk.

References

1. Varbo A, Benn M, Tybjaerg-Hansen A, Jorgensen 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.

2. Proctor SD, Vine DF,MamoJC. Arterial retention of apolipoprotein B (48)- and B (100)-containing lipoproteins in atherogenesis. Curr Opin Lipidol 2002;13:461–70.

3. Tabas I, Williams KJ, Boren J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 2007;116:1832– 44.

4. Varbo A, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. Elevated remnant cholesterol causes both low grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation. Circulation 2013;128:1298 –309.

Key words

remnant cholesterol; residual risk; LDL cholesterol; mortality risk; ischaemic heart disease