Abstract
BackgroundAs the approach to low-density lipoprotein cholesterol (LDL-C) lowering becomes increasingly intensive, accurate assessment of LDL-C at very low levels warrants closer attention in individualized clinical efficacy and safety evaluation. We aimed to assess the accuracy of LDL-C estimation at very low levels by the Friedewald equation, the de facto clinical standard, and compare its accuracy with a novel, big data-derived LDL-C estimate.MethodsIn 191,333 individuals with Friedewald LDL-C < 70 mg/dL, we compared the accuracy of Friedewald and novel LDL-C values in relation to direct measurements by Vertical Auto Profile ultracentrifugation. We examined differences (estimate minus ultracentrifugation) and classification according to levels initiating additional safety precautions per clinical practice guidelines.ResultsFriedewald values were less than ultracentrifugation measurement, with a median difference (25th to 75th percentile) of –2.4 (–7.4 to 0.6) at 50–69 mg/dL, –7.0 (–16.2 to –1.2) at 25–39 mg/dL, and –29.0 (–37.4 to –19.6) at < 15 mg/dL. The respective values by novel estimation were –0.1 (–1.5 to 1.3), –1.1 (–2.5 to 0.3), and –2.7 (–4.9 to 0.0) mg/dL. Among those with Friedewald LDL–C < 15, 15 to < 25, and 25 to < 40 mg/dL, the classification was discordantly low in 94.9%, 82.6%, and 59.9% of individuals as compared with 48.3%, 42.4%, and 22.4% by novel estimation.ConclusionsEstimation of even lower LDL-C values (by Friedewald and novel methods) is even more inaccurate. More often than not, a Friedewald value < 40 mg/dL is underestimated, which translates into unnecessary safety alarms that could be reduced in half by estimation using our novel method.
Highlights
As the approach to low-density lipoprotein cholesterol (LDL-C) lowering becomes increasingly intensive, accurate assessment of LDL-C at very low levels warrants closer attention in individualized clinical efficacy and safety evaluation
Study population We examined consecutive lipid profiles from US patients aged 18 years or older in the Very Large Database of Lipids, which has lipid distributions that are similar to the National Health and Nutrition Examination Survey population (NHANES) 2007–2008 [28]
Correlation between LDL-C values and direct ultracentrifugation measurement Overall, LDLd-C appeared more strongly correlated with LDLn-C (Rho = 0.9401, P < 10–15) than with
Summary
As the approach to low-density lipoprotein cholesterol (LDL-C) lowering becomes increasingly intensive, accurate assessment of LDL-C at very low levels warrants closer attention in individualized clinical efficacy and safety evaluation. As more aggressive LDL-C lowering approaches become increasingly common, with use of human monoclonal antibodies targeting proprotein convertase subtilisin-kexin type 9 (PCSK9) [12,13,14], the accuracy of LDL-C assessment at very low levels gains importance. The Food and Drug Administration (FDA) recommended close monitoring for adverse events at these very low LDL-C levels in order to track any potential long-term safety effects [14, 18]. Accurate assessment of LDL-C at very low levels is directly tied to the accuracy of therapeutic dosing and the attention to safety monitoring
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