Author + information
- Jeffrey W. Meeusen, PhD∗ (, )
- Leslie J. Donato, PhD and
- Allan S. Jaffe, MD
- ↵∗Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905
The paper by Robinson et al. (1) suggested that low-density lipoprotein cholesterol (LDL-C) values <25 mg/dl were not associated with adverse neurocognitive events. The impact of lipid-lowering medication on cognitive function is an area of ongoing research with mixed evidence. A separate meta-analysis including a similar collection of clinical trials found a significantly increased risk of adverse neurocognitive events among patients treated with PCSK9 inhibitors (2).
The concern over cognitive impact and lipid-altering drugs is based on the reduced availability of lipid-soluble nutrients in the circulation. PCSK9 inhibitors offer new lows for lipids, with endpoint LDL-C values <30 mg/dl in many patients. The study by Robinson et al. (1) compared patients with LDL-C concentrations of <15 mg/dl and <25 mg/dl.
The primary endpoint for the PCSK9 inhibitor trials reviewed was reduction of calculated LDL-C. Studies accounted for the documented underestimation of calculated LDL-C by measuring LDL-C by ultracentrifuge separation. Robinson et al. (1) reported a median difference of only 3 mg/dl between calculated versus measured LDL-C across all patients and, thus, suggested that the underestimation did not play a significant role.
However, the variability in differences between measured and calculated values is significantly greater at lower LDL-C concentrations (3). Based on our data, a calculated LDL-C of 25 mg/dl can have an actual measured LDL-C value between 7 and 45 mg/dl. This phenomenon is actually supported in their report as the range of discrepancies spanned from −14 mg/dl to +160 mg/dl for patients with LDL-C concentrations of <15 mg/dl compared with −24 mg/dl to +26 mg/dl when LDL-C was between 15 and 25 mg/dl.
Misclassification of even small numbers of patients could skew the data significantly for this analysis of cognitive abnormalities. It would be important to rely on the measured LDL-C concentrations to compare patients with neurocognitive events to those without. More importantly, providers and patients should be aware of the limitations of calculated LDL-C when managing patients with very low concentrations of LDL-C.
Please note: Dr. Jaffe is a consultant for and has received honoraria from Abbott, Alere Beckman, ET Healthcare, NeurogenomeX, Novartis, Roche, Siemens, Sphingotec, theheart.org, and Singulex. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. P.K. Shah, MD, served as Guest Editor-in-Chief for this paper. Robert Giugliano, MD, served as Guest Editor for this paper.
- 2017 American College of Cardiology Foundation
- Robinson J.G.,
- Rosenson R.S.,
- Farnier M.,
- Chaudhari U.,
- Sasiela W.J.,
- Merlet L.,
- et al.
- Khan A.R.,
- Bavishi C.,
- Riaz H.,
- Farid T.A.,
- Khan S.,
- Atlas M.,
- et al.