Variability of lipid levels is predictive of CV events
Visit-to-visit variability of lipid measurements as predictors of cardiovascular events Presented in part at the American Heart Association Annual Scientific Sessions, November 2017.Waters DD, Bangalore S, Fayyad R, et al. - J Clin Lipidol 2018;12:356–366
Introduction and methods
Long-term variability of total cholesterol and LDL-c levels have been associated with an increased risk of CV events [1,2]. However, it is not known, whether variations of HDL-c and triglyceride (TG) levels are also linked to increased CV risk.
This post hoc analysis of the Treating to New Targets (TNT) trial [3,4 evaluated whether HDL-c and TG variability predict coronary and CV events, and incident diabetes, in 9572 patients. Moreover, the correlation among LDL-c, HDL-c and TG variability was assessed, and the relative strength of these measures of variability in predicting CV events was investigated.
In the TNT trial, patients aged 35-75 years with clinically evident coronary disease and elevated lipid levels were randomly assigned to atorvastatin 10 mg or 80 mg/day, and followed up for a median of 4.9 years. The main measure of lipid variability for this analysis was the average successive variability (ASV), defined as the average absolute difference between successive values of the available HDL-c, TG, or LDL-c levels.
The primary outcome was the occurrence of any coronary event, defined as coronary heart disease death, nonfatal myocardial infarction (MI), resuscitated cardiac arrest, revascularization, or angina. The secondary outcomes were any CV event (any coronary event or cerebrovascular event, peripheral vascular disease, hospitalization for heart failure), death, MI, stroke, or incident diabetes.
- For each 1 SD increase in ASV of HDL-c, the risk of any coronary event increased (HR: 1.06; 95%CI: 1.02–1.10; P=0.0053; HRadj: 1.16; 95%CI: 1.11–1.21; P<0.0001). Similarly, for each 1 SD increase in ASV of TG the HR was 1.11 (95%CI: 1.08–1.14; P<0.0001; HRadj: 1.09; 95%CI: 1.04–1.15; P=0.0005), and for each 1 SD increase in ASV of LDL-c, the HR was 1.14 (95%CI: 1.10–1.18; P<0.0001; HRadj: 1.14; 95%CI: 1.09–1.19; P<0.0001).
- The risk for any coronary event was 50% higher in quintile 5 of ASV for HDL-c compared to quintile 1 (HRadj: 1.50; 95%CI: 1.30–1.74; P<0.0001).
- For each of the secondary endpoints except for new-onset diabetes, the HR was higher in quintile 5 of ASV for HDL-c compared to quintile 1, ranging from 1.56 to 1.81, and in each case, the trend across quintiles was highly statistically significant.
- Quintile 5 of ASV for TG was associated with an increased risk for any coronary event compared to quintile 1 (HRadj: 1.35; 95%CI: 1.14–1.60; P<0.0006).
- For secondary outcomes any CV event, stroke, non-fatal MI and incident diabetes, the HR was higher in quintile 5 of ASV for TG compared to quintile 1, ranging from 1.31 to 1.98, and in each case, the trend across quintiles was highly statistically significant.
- For all-cause mortality, there was a lower HR in quintile 5 of ASV for TG compared to quintile 1 (HR: 0.89; 95%CI: 0.64–1.25; P<0.51). This finding may be a result of the shorter follow-up and thus fewer lipid measurements among patients who died.The risk for any coronary event was 24% higher in quintile 5 of ASV for LDL-c compared to quintile 1 (HR:1.25; 95%CI:1.07-1.44, P=0.0037)
- For incident diabetes, the HR for quintile 5 compared to quintile 1 for ASV of LDL-c was 1.30 (95%CI: 0.99–1.71; P<0.060).
- The correlation between TG and HDL-c variability was 0.046, between TG and LDL-c variability was 0.26, and between HDL-c and LDL-c variability was 0.16 (P <0.0001 for all).
- HDL-c and LDL-c variability as predictors of time to first coronary event: the HR for 1 SD increase in ASV for HDL-c was 1.13 (95%CI: 1.07–1.18; P<0.0001), for LDL-c was 1.10 (95%CI: 1.05–1.16; P<0.0001), and for TG variability was 1.05 (95%CI: 1.00–1.11; P<0.0495).
Visit-to-visit variability in fasting measurements of HDL-c, TG, and LDL-c are predictive of coronary events, CV events, and TG and LDL-c variability, are also predictive of incident diabetes. The mechanisms accounting for these associations remain to be determined.