Comparison of low-density lipoprotein cholesterol equations in patients with dyslipidaemia receiving cholesterol ester transfer protein inhibition

Abstract

Aims: Low-density lipoprotein (LDL-C) lowering is imperative in cardiovascular disease prevention. We aimed to compare accuracy of three clinically-implemented LDL-C equations in a clinical trial of cholesterol ester transfer protein (CETP) inhibition.

Methods and results: Men and women aged 18-75 years with dyslipidaemia were recruited from 17 sites in the Netherlands and Denmark. Patients were randomly assigned to one of nine groups using various combinations of the CETP inhibitor TA-8995 (obicetrapib), statin therapy, and placebo. In pooled measurements over 12 weeks, we calculated LDL-C by the Friedewald, Martin/Hopkins, and Sampson equations, and compared values with preparative ultracentrifugation (PUC) LDL-C overall and with a special interest in the low LDL-C/high triglycerides subgroup. There were 242 patients contributing 921 observations. Overall median LDL-C differences between estimates and PUC were small: Friedewald, 0.00 (25th, 75th: -0.10, 0.08) mmol/L [0 (-4, 3) mg/dL]; Martin/Hopkins, 0.02 (-0.08, 0.10) mmol/L [1 (-3, 4) mg/dL]; and Sampson, 0.05 (-0.03, 0.15) mmol/L [2 (-1, 6) mg/dL]. In the subgroup with estimated LDL-C <1.8 mmol/L (<70 mg/dL) and triglycerides 1.7-4.5 mmol/L (150-399 mg/dL), the Friedewald equation underestimated LDL-C with a median difference versus PUC of -0.25 (-0.33, -0.10) mmol/L [-10 (-13, -4) mg/dL], whereas the median difference by Martin/Hopkins was 0.00 (-0.08, 0.10) mmol/L [0 (-3, 4) mg/dL] and by Sampson was -0.06 (-0.13, 0.00) mmol/L [-2 (-5, 0) mg/dL]. In this subgroup, the proportion of LDL-C observations <1.8 mmol/L (<70 mg/dL) that were correctly classified compared with PUC was 71.4% by Friedewald vs. 100.0% by Martin/Hopkins and 93.1% by Sampson.

Conclusion: In European patients with dyslipidaemia receiving a CETP inhibitor, we found improved LDL-C accuracy using contemporary equations vs. the Friedewald equation, and the greatest accuracy was observed with the Martin/Hopkins equation.

Registration: ClinicalTrials.gov, NCT01970215.

Keywords: Accuracy; Cholesterol ester transfer protein inhibition; Friedewald equation; Low-density lipoprotein cholesterol; Martin/Hopkins equation; Sampson equation.

Figure 1

TULIP trial profile and low-density lipoprotein cholesterol accuracy analysis population. The figure depicts the flow of patients through the TULIP trial and the analysis population, which includes all available low-density lipoprotein cholesterol observations. Observations are defined as blood samples with available standard lipid profile data to estimate low-density lipoprotein cholesterol and direct measurement of low-density lipoprotein cholesterol by preparative ultracentrifugation. TULIP, TA-8995 in Patients with Mild Dyslipidaemia; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides.

Figure 2

Waterfall plot of differences between low-density lipoprotein cholesterol estimates and preparative ultracentrifugation. Differences are shown in mmol/L overall for each low-density lipoprotein cholesterol equation and in subgroups with estimated low-density lipoprotein cholesterol  <1.8 mmol/L (<70 mg/dL) and triglyceride levels 1.7–4.5 mmol/L (150–399 mg/dL). Difference in low-density lipoprotein cholesterol vs. preparative ultracentrifugation = (low-density lipoprotein cholesterol by specified equation method)—(low-density lipoprotein cholesterol by preparative ultracentrifugation). PUC, preparative ultracentrifugation; LDL-C, low-density lipoprotein cholesterol.

Figure 3

Proportion of low-density lipoprotein cholesterol levels classified by the equations as < or ≥1.8 mmol/L (70 mg/dL) that were correctly classified when compared with preparative ultracentrifugation in patients with triglyceride levels of 1.7–4.5 mmol/L (150–399 mg/dL). N’ = number of records in the double-blind treatment period with an LDL-C measurement by preparative ultracentrifugation and Friedewald, for the given category. LDL-C, low-density lipoprotein; PUC, preparative ultracentrifugation.