Triglyceride-Rich Lipoprotein Cholesterol and Risk of Cardiovascular Events Among Patients Receiving Statin Therapy in the Treating to New Targets (TNT) Trial
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.
Clinical Trial Registration—URL: https://clinicaltrials.gov Unique Identifier: NCT00327691
- Triglyceride-rich lipoproteins
- Non-HDL cholesterol
- cardiovascular risk
- TNT trial
- statin therapy
- Received October 19, 2017.
- Revision received March 3, 2018.
- Accepted March 21, 2018.