• Analysis Backs Use of Remnant Cholesterol Levels to Predict Future Risk of MI, IHD

    The development of a cardiovascular risk algorithm such as SCORE or PCE) including remnant cholesterol together with low-density lipoprotein (LDL) cholesterol would help to better identify high-risk individuals who could be candidates for statins in a primary prevention setting, a new analysis of population data suggests.

    The study, published online Monday and in the June 21 issue of the Journal of the American College of Cardiology, reports the use of elevated levels of remnant cholesterol as a risk marker appropriately reclassified up to 40% of patients without a history of ischemic cardiovascular disease, diabetes or statin therapy who later experienced ischemic heart disease (IHD) or myocardial infarction (MI).

    Led by Takahito Doi, MD, PhD, from Copenhagen University Hospital, Denmark; the University of Copenhagen; and the National Cerebral and Cardiovascular Center, Osaka, Japan, the team behind the research noted that remnant cholesterol is calculated by taking a measure of total cholesterol and subtracting LDL cholesterol and high-density lipoprotein (HDL) cholesterol, leaving the cholesterol content of the triglyceride-rich very-low-density lipoproteins, intermediate-density lipoproteins and chylomicron remnants in the non-fasting state.

    “When these particles enter the arterial wall, they are taken up by macrophages to produce foam cells, and therefore elevated remnant cholesterol likely enhance accumulation of cholesterol in the arterial wall, leading to progression of atherosclerosis and in consequence ischemic heart disease,” said Doi and colleagues.

    “Most guidelines for assessment of the 10-year risk of ischemic heart and atherosclerotic cardiovascular disease include levels of total and HDL cholesterol. However, remnant cholesterol levels are not included.”

    However, the new report suggests that risk stratification of IHD using remnant cholesterol levels in addition to conventional risk factors could improve the selection of individuals for statin therapy appropriately, “which may contribute to a reduction in the burden of ischemic heart disease for long periods.”

    Study setup

    Doi and colleagues tested the hypothesis that the inclusion of elevated remnant cholesterol will lead to a reclassification of individuals who later experience myocardial infarction and IHD in a cohort of 41,928 white Danish individuals from the Copenhagen General Population Study without a history of ischemic cardiovascular disease, diabetes and statin use at baseline, who were followed up for at least 10 years. The median follow-up time was 12.0 years (interquartile range [IQR]: 10.7-13.5 years).

    Using predefined cut points for elevated remnant cholesterol, the team calculated net reclassification index (NRI) from below to above 5%, 7.5%, and/or 10%, 10-year occurrence of MI and IHD (defined as a composite of death from IHD, MI, and coronary revascularization).

    In the baseline model, covariates for adjustment were chosen according to known associations with IHD, including: age (average age of 57), sex (57% women), smoking status (22% current smokers), LDL cholesterol (average 3.3 mmol/L), and systolic blood pressure (average 140 mm Hg).

    The team noted that HDL cholesterol was deliberately omitted as covariate for adjustment in the main analysis because it influences lipid traits through biological pathways, noting that HDL cholesterol levels are inversely related to plasma triglycerides and remnant cholesterol levels.

    The study reported 1,063 first-time MI events and 1,460 and first-time IHD events during the first 10 years of follow-up.

    Key findings

    Doi and colleagues reported that for remnant cholesterol levels in the 95th percentile or above (≥1.6 mmol/L, 61 mg/dL) or the 75th percentile and above (≥1.0 mmol/L, 37 mg/dL), the multivariable adjusted hazard ratios were 1.58 (95% confidence interval [CI]: 1.27-1.98) and 1.48 (95% CI: 1.29-1.69) for MI and 1.49 (95% CI: 1.23-1.81) and 1.43 (95% CI: 1.27-1.60) for IHD, respectively, in comparison with individuals with remnant cholesterol levels in the bottom 50th percentile (<0.6 mmol/L, <25 mg/dL).

    They added that for individuals with remnant cholesterol levels in the 95th percentile or above, 23% of MI (P < 0.001) and 21% of IHD (P < 0.001) were reclassified correctly from below to above 5% for 10-year occurrence when remnant cholesterol levels were added to models based on conventional risk factors, whereas no events were reclassified incorrectly.

    As a result, they said the addition of remnant cholesterol levels resulted in NRI of 10% (95% CI: 1%-20%) for MI and 5% (95% CI: -3% to 13%) for IHD.

    “We found that elevated remnant cholesterol appropriately reclassified up to 40% of those who later experienced myocardial infarction and ischemic heart disease, leading to NRI of up to 20% in statin-naïve individuals without a history of ischemic cardiovascular disease and diabetes,” said the team, noting that when reclassifications were combined from below to above 5%, 7.5% and 10% risk of events, 42% (P < 0.001) of individuals with MI and 41% (P < 0.001) with IHD were reclassified appropriately, leading to NRI of respectively 20% (95% CI: 9% to 31%) and 11% (95% CI: 2% to 21%).

    “These novel results in individuals with elevated remnant cholesterol suggest that adding this causal risk factor to guideline prediction models will improve the identification of individuals who would benefit the most from statin treatment,” said Doi and colleagues, commenting that both doctors and patients should be aware of remnant cholesterol levels to prevent future risk of MI and IHD.

    They suggested that the development of a cardiovascular risk algorithm (such as SCORE or PCE) including remnant cholesterol together with LDL cholesterol “would help to better identify high-risk individuals who could be candidates for statins in a primary prevention setting.”

    They added that remnant cholesterol can be calculated with a standard lipid profile, and without additional cost, meaning that the use of remnant cholesterol is easy to introduce into daily clinical practice.

    They noted that further research is now needed to assess the efficacy of statin therapy in individuals without diabetes or manifest ischemic cardiovascular disease whose risk of disease is reclassified as high when remnant cholesterol is added to the conventional risk model.

    Next steps

    Writing in an accompanying editorial, Peter W.F. Wilson, MD, and Alan T. Remaley, MD, PhD, from the Emory University School of Medicine, Atlanta, said the Bayesian reclassification analyses used by Doi and colleagues demonstrate that non-fasting specimens can be used to predict initial ischemic cardiovascular disease events in Danish adults and that elevated remnant cholesterol was associated with approximately 20% reclassification of IHD events.

    The editorialists noted that very elevated levels (above the 75th percentile) of non-fasting remnant cholesterol, or non-fasting triglyceride, deserve further evaluation as a potentially valuable modifier of atherosclerotic cardiovascular disease risk, adding that both are discussed in the 2019 U.S. guideline on the management of blood cholesterol.

    “The reported findings rekindle interest in atherogenic non-fasting lipid measurements and emphasize an important role for elevated non-fasting remnant cholesterol, estimated from non-fasting triglyceride, as a value-added predictor of ischemic events,” they said.

    “Replication of the findings, especially in adults without IHD, without diabetes, and not on lipid-altering therapy, could move these findings forward to potentially improve prognostication and care for patients at risk for IHD events.”


    Doi T, Langsted A, Nordestgaard BG. Elevated Remnant Cholesterol Reclassifies Risk of Ischemic Heart Disease and Myocardial Infarction. J Am Coll Cardiol 2022;79:2383-2397.

    Wilson PWF, Remaley AT. Ischemic Heart Disease Risk and Remnant Cholesterol Levels.  J Am Coll Cardiol 2022;79:2398-2400.

    Image Credit: jarun011 – stock.adobe.com

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