• VLDL, Remnant Cholesterol Might Better Predict Atherosclerotic Cardiovascular Risk Than LDL, 2 Large-Scale Studies Show

    Two separate studies published on Monday suggest that very-low-density lipoprotein (VLDL) and remnant cholesterol could be better predictors of atherosclerotic cardiovascular disease (ASCVD) risk than the long-used biomarker low-density lipoprotein cholesterol (LDL-C).

    However, the authors in an accompanying editorial to the two studies warned that it would be “premature” to shelve LDL-C as a measure based on the results.

    The studies were published in the Dec 8. issue of the Journal of the American College of Cardiology.

    One, led by University of Copenhagen and Copenhagen University Hospital’s Mie Balling, MD,  followed 25,480 individuals from the Copenhagen General Population Study (CGPS), who were not on lipid-lowering therapy and had no history of myocardial infarction (MI) at baseline, for a median 11 years. Of these, 1,816 were diagnosed with MI.

    The researchers found that VLDL cholesterol was responsible for 46% of MI risk.

    The other study assessed observational data over 263 major adverse cardiovascular events (MACEs) in the 6,901-subject high-risk primary prevention PREDIMED (Prevención con Dieta Mediterránea) trial population after a median follow-up of 4.8 years.

    The researchers, led by Olga Castañer, MD, PhD, of the Hospital del Mar Medical Research Institute, Barcelona, and Spain’s Center for Biomedical Research Network (CIBER), found that blood levels of triglycerides (TG) and remnant cholesterol in overweight and obese subjects at high cardiovascular risk were independently associated with cardiovascular outcomes. LDL-C and high-density lipoprotein cholesterol (HDL-C) were not.

    The research follows a “renaissance” of plasma TG as a risk factor for ASCVD in recent lipidology development, alongside a consensus opinion that HDL is no longer an independent direct actor in ASCVD; but is still an predictor of risk, John Burnett, MD, PhD, of the University of Western Australia, and colleagues noted in the accompanying editorial.

    LDL-C, on the other hand, is “relatively well understood” as a risk factor, they said, adding that the results are therefore somewhat unexpected, particularly in the PREDIMED study, in which neither LDL cholesterol nor HDL were associated with MACE.

    The CGPS study did list LDL-C risk to some extent, though finding that its cardiovascular effects were much lower than VLDL cholesterol.


    Balling and colleagues’ analysis of a 25,480-person subpopulation within the 109,751-person CGPS database tested the hypothesis that VLDL cholesterol and TG each explain part of the MI risk from the composite measure known as plasma apolipoprotein B (apoB) – all apoB-containing lipoproteins causing cardiovascular disease.

    All on the registry had measurements of plasma apoB, and cholesterol and TG content of VLDL, intermediate-density lipoproteins (IDLs), and LDLs.

    The researchers concluded that VLDL cholesterol statistically explained 46% (95% confidence interval [CI]: 21% to 72%; p = 0.001) of the associated risk between apoB-containing lipoproteins and MI in models adjusted for age and sex, while IDL and LDL cholesterol accounted for 25% (95% CI: 10% to 39%; p = 0.001). On a multivariable-adjusted basis, the same measures were 50% and 29%, respectively.

    VLDL TG was not associated with risk, however, while remnant cholesterol explained 10% of MI risk in a corresponding model (95% CI: 0% to 24%; p = 0.17).

    It meant that VLDL cholesterol was the most important MI risk factor in the CGPS data, accounting for a substantial fraction of causal MI risk in patients with elevated apoB-containing lipoproteins, whereas VLDL TG did not. VLDL cholesterol was also riskier for MI ahead of systolic blood pressure, smoking and IDL plus LDL cholesterol, the editorialists noted.

    The research was funded partly by the Novo Nordisk Foundation, part of the Danish biopharma company that is heavily invested in diabetes, cardiovascular and obesity therapeutics. One of the researchers is a Novo Nordisk employee, while another is hired on a consultancy basis with the firm, as well as with other pharma. The Danish Heart Foundation also provided funding for the study.

    The funders did not participate in the design or conduct of the study or the paper, the researchers said.


    PREDIMED, a Spanish interventional trial, assesses the links between TG and remnant cholesterol with cardiovascular outcomes in the context of the effects of a Mediterranean diet on ASCVD prevention.

    The researchers determined starting lipid profile using frozen samples taken at baseline, before searching for MACE – the primary endpoint – in the trial population, with a mean age of 67 years, body mass index of 30 kg/ m2, 43% of whom were men and 48% had diabetes.

    MACE events occurred in 263 (3.8%) of the participants. According to multivariable-adjusted Cox analyses, MACE was associated with TG (hazard ratio [HR]: 1.04; 95% CI: 1.02 to 1.06 per 10 mg/dl [0.11 mmol/l]; p < 0.001), non-HDL-C (HR: 1.05; 95% CI: 1.01 to 1.10 per 10 mg/dl [0.26 mmol/l]; p = 0.026), and remnant cholesterol (HR: 1.21; 95% CI: 1.10 to 1.33, per 10 mg/dl [0.26 mmol/l]; p < 0.001).

    However, LDL-C and HDL-C were not associated with MACEs.

     “Our results showed that levels of triglycerides and estimated remnant-C (cholesterol), but not LDL-C or HDL-C, were associated with CVD outcomes independently of lifestyle characteristics and other cardiovascular risk factors in a cohort of Mediterranean (diet) subjects at high risk with a high prevalence of diabetes and obesity,” the researchers said.

    “Remnant-C should be considered a preferential treatment target in this population,” they stressed, pushing for randomized controlled trials with hard cardiovascular outcomes to compare the benefit of remnant-C lowering interventions versus standard cholesterol-lowering therapy.

    The authors list a range of pharmaceutical company links in the diabetes and cardiovascular space.

    Meaning in practice

    The editorialists highlighted the importance of the complimentary results despite the data sets being distinct in design and analytical methods.

    Nevertheless, they warned LDL-C should not be set aside as a predictor for ASCVD risk.

    “Notably, TG within VLDL was not associated with ASCVD events. Thus, in contrast to PREDIMED, CGPS gives LDL some credit, even if it seems dwarfed by the effect of VLDL cholesterol,” they said.

    The editorialists added that the PREDIMED data include just 263 total MACE events – “insufficient to offset the mountain of literally hundreds of studies and independent types of experiments that uphold the value of LDL cholesterol in prediction and intervention of ASCVD”.

    If results of CGPS can be replicated, they could herald an advance in the diagnosis and prevention of ASCVD endpoints, the editorialists wrote.

    “One could envision a future where in addition to the routine lipid profile, newer analytes such as remnant cholesterol as well as lipoprotein(a) and apo B are reported to improve prognostication and help guide preventive treatments.”


    Castañer O, Pintó X, Subirana I, et al. Remnant Cholesterol, Not LDL Cholesterol, Is Associated With Incident Cardiovascular Disease. J Am Coll Cardiol 2020;76:2712-24.

    Balling M, Afzal S, Varbo A, et al. VLDL Cholesterol Accounts for One-Half of the Risk of Myocardial Infarction Associated With apoB-Containing Lipoproteins. J Am Coll Cardiol 2020;76:2725-35.

    Burnett JR, Hooper AJ and Hegele RA. Remnant Cholesterol and Atherosclerotic Cardiovascular Disease Risk. J Am Coll Cardiol 2020;76:2736-9.

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