Background—Mendelian randomization data suggest genetic determinants of lifetime higher triglyceride-rich lipoprotein-cholesterol (TRL-C) are causally related to cardiovascular disease and therefore a potential therapeutic target. The relevance of TRL-C among patients receiving statins is unknown. We assessed the relationship between TRL-C and cardiovascular risk, and whether this risk was modifiable among patients receiving statins in the TNT trial.

Methods—Patients with coronary heart disease [CHD] and LDL-C 130-250mg/dL entered an 8-week run-in phase with atorvastatin 10mg/day (ATV10). After this period, participants with LDL-C <130mg/dL entered the randomised phase with ATV10 (n=5006) vs. atorvastatin 80mg/day (ATV80, n=4995). Primary endpoint: CHD death, non-fatal myocardial infarction, resuscitated cardiac arrest, or stroke (major adverse cardiovascular events [MACE]). TRL-C was calculated as total cholesterol minus HDL-C minus LDL-C. The effect of atorvastatin on TRL-C was assessed during the run-in phase (ATV10) and randomised phase (ATV80 vs. ATV10). The risk of MACE was assessed across quintiles (Q) of baseline TRL-C (and, for comparison, by baseline triglycerides and non-HDL-C) during the randomised period. Finally, the association between TRL-C changes with atorvastatin and cardiovascular risk was assessed by multivariate Cox-regression.

Results—ATV10 reduced TRL-C a 10.7% from an initial TRL-C of 33.9±16.6 mg/dL. ATV80 led to an additional 15.4% reduction. Cardiovascular risk factors positively correlated with TRL-C. Among patients receiving ATV10, higher TRL-C associated higher 5-year MACE rates (Q1=9.7%, Q5=13.8%; HR Q5-vs-Q1: 1.48 [95%CI 1.15-1.92]; p-trend<0.0001). ATV80 (vs. ATV10) did not significantly alter the risk of MACE in Q1-Q2, but significantly reduced risk in Q3-Q5 (RRR: 29%-41%; all p<0.0250), with evidence of effect modification (p-homogeneity=0.0053); results were consistent for triglycerides (p-homogeneity=0.0101) and directionally similar for non-HDL-C (p-homogeneity=0.1387). Finally, in adjusted analyses, a 1SD percentage reduction in TRL-C with atorvastatin resulted in a significant lower risk of MACE (HR 0.93, 95%CI 0.86-1.00, p=0.0482) independent of the reduction in LDL-C and of similar magnitude to that per 1SD lowering in LDL-C (HR 0.89, 95%CI 0.83-0.95, p=0.0008).

Conclusions—The present post-hoc analysis from TNT shows that increased TRL-C levels associate an increased cardiovascular risk and provides evidence for the cardiovascular benefit of lipid-lowering with statins among CHD patients with high TRL-C.