Direct or calculated remnant cholesterol: does it matter?

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9 August 2021

In this report from the Copenhagen General Population Study, direct measurement of remnant cholesterol identifies an additional 5% of individuals in the general population with cholesterol-rich, triglyceride (TG)-poor remnants who are at increased risk of myocardial infarction.

Varbo A, Nordestgaard BG. Directly measured vs. calculated remnant cholesterol identifies additional overlooked individuals in the general population at higher risk of myocardial infarction. Eur Heart J 2021 ; doi: 10.1093/eurheartj/ehab293. Online ahead of print.

STUDY SUMMARY

Objective:

To investigate whether elevated directly measured remnant cholesterol is associated with increased risk of ischaemic heart disease and myocardial infarction (MI) in the general population. A secondary aim was to investigate whether this measure was superior to calculated remnant cholesterol in identifying individuals at increased cardiovascular risk.

Study design:

The Copenhagen General Population study is a prospective observational study.

Study population:

16 207 individuals (54% women, median age 56 years) from the Copenhagen General Population Study with both directly measured and calculated remnant cholesterol, with 11 years (range 0–14 years) median follow-up.

Main study variables:

· Directly measured remnant cholesterol

· Calculated remnant cholesterol, defined as total cholesterol – (low-density lipoprotein cholesterol + high-density lipoprotein cholesterol)

· Ischaemic heart disease (IHD) and myocardial infarction (MI)

Methods:

Hazard ratios for IHD and MI were estimated using Cox proportional hazards regression models, excluding individuals with pre-existing IHD or MI at baseline. Besides age adjustment, hazard ratios were adjusted for possible confounders, including sex, systolic and diastolic blood pressure, antihypertensive therapy, lipid-lowering therapy, and smoking. Discordance for the risk of MI between directly measured and calculated remnant cholesterol was investigated by Cox proportional hazard regression models with individuals divided into four groups with a focus on high levels (individuals with the 20% highest levels): (i) individuals with both directly measured and calculated remnant cholesterol <80th percentile (reference), (ii) individuals with directly measured remnant cholesterol ≥80th percentile but calculated remnant cholesterol <80th percentile, (iii) individuals with calculated remnant cholesterol ≥80th percentile but directly measured remnant cholesterol <80th percentile, and (iv) individuals with both directly measured and calculated remnant cholesterol ≥80th percentile.

Results:

Higher directly measured or calculated remnant cholesterol levels were associated with increased risk for IHD and MI. Hazard ratios for individuals with concentrations >95th percentile versus <40th percentile were 1.75 (95% confidence interval [CI] 1.42–2.15) and 1.76 (1.42–2.17) for IHD, and 2.05 (1.50 –2.80) and 1.93 (1.40–2.66) for MI, respectively.

The association between directly measured and calculated remnant cholesterol showed discordance at high concentrations. Overall, 5% of individuals had only high directly measured remnant cholesterol and 5% had only high calculated remnant cholesterol. Individuals with only high directly measured remnant cholesterol were at higher risk for MI and IHD compared with those with only high calculated remnant cholesterol (Table).

Table. Risk for IHD and MI with high remnant cholesterol (C).

Hazard ratios with 95% confidence intervals

	Only high directly measured remnant-C	Only high calculated remnant-C
Risk for MI*	1.83 (1.35–2.47)	1.14 (0.80–1.62)
Risk for IHD*	1.42 (1.15–1.75)	1.14 (0.91–1.44)

* Comparison to individuals with both directly measured and calculated remnant cholesterol <80th percentile for IHD and for MI; C cholesterol

High was defined as ≥80th percentile

Prediction of 10-year risk of MI was improved by adding directly measured or calculated remnant cholesterol to a model including the conventional risk factors. When using a cut point ≥80th percentile for directly measured or calculated remnant cholesterol, the net reclassification index was 4.7% (1.4–8.0%; p= 0.006) and 7.5% (3.5–11.5%; p< 0.001), respectively.

Author conclusion:

High concentrations of both directly measured and calculated remnant cholesterol are associated with higher risk of IHD and MI. Furthermore, directly measured vs. calculated remnant cholesterol identifies 5% of overlooked individuals in the general population with cholesterol-rich, TG-poor remnants and 1.8-fold increased risk of MI.

COMMENT

Remnant cholesterol, defined as the cholesterol contained in TG-rich lipoprotein remnants, which include chylomicron remnants, very low-density lipoproteins (VLDL), and intermediate-density lipoproteins (IDL), has attracted renewed focus with accumulating evidence supporting an association with cardiovascular disease. Indeed, the totality of evidence from observational studies and genetic analyses shows that elevated remnant cholesterol is a causal risk factor (1-4). Definitive proof is still required, however, from cardiovascular outcomes studies, such as PROMINENT (5).

The availability of new assays for direct measurement of remnant cholesterol underlines the need to test whether the association of calculated remnant cholesterol with cardiovascular risk also applies to directly measured remnant cholesterol. Furthermore, there is also the need to investigate whether inclusion of directly measured remnant cholesterol adds to cardiovascular risk estimation.

The current study tested both questions. First, the researchers showed that directly measured elevated remnant cholesterol is also associated with increased cardiovascular risk, similar to that reported for calculated remnant cholesterol. Second, they showed that compared with calculated remnant cholesterol, directly measured remnant cholesterol identifies a further 5% of the general population with high remnant cholesterol and correspondingly high risk for MI, and therefore adds value to risk prediction scores.

The findings are pertinent to the PROMINENT study with pemafibrate, which has incorporated use of directly measured remnant cholesterol in the study methodology. Results from this study will provide a true test whether lowering directly measured remnant cholesterol reduces cardiovascular risk in statin-treated diabetic patients with atherogenic dyslipidemia.

References

1. 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.

2. Varbo A, Nordestgaard BG. Remnant cholesterol and risk of ischemic stroke in 112,512 individuals from the general population. Ann Neurol 2019;85:550-9.

3. Jørgensen AB, Frikke-Schmidt R, West AS, et al. Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. Eur Heart J 2013;34:1826–33.

4. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547–63.

5. Pradhan AD, Paynter NP, Everett BM, et al. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. Am Heart J 2018;206:80–93.

Key words

remnant cholesterol; direct assay; cardiovascular risk; PROMINENT