Visit-to-Visit LDL Cholesterol Variability and Risk of Cardiovascular Outcomes: Insights From TNT Trial | Journal Scan

Study Questions:

What is the role of visit-to-visit variability in low-density lipoprotein cholesterol (LDL-C) levels on cardiovascular outcomes?


The TNT (Treating to New Targets) trial enrolled patients with coronary artery disease (CAD) and LDL-C <130 mg/dl and randomized them to atorvastatin 80 mg/d versus 10 mg/d. Visit-to-visit LDL-C variability was evaluated from 3 months into randomization using various measures of LDL-C variability with standard deviation (SD) and average successive variability (ASV) used as the primary measures. Primary outcome was any coronary events, and secondary outcomes were any cardiovascular event, death, myocardial infarction (MI), or stroke.


Among 9,572 patients, SD and ASV were significantly lower with atorvastatin 80 mg/d vs. 10 mg/d (SD: 12.03 ± 9.70 vs. 12.52 ± 7.43; p = 0.005; ASV: 12.84 ± 10.48 vs. 13.76 ± 8.69; p < 0.0001). In the adjusted model, each 1-SD increase in LDL-C variability (by ASV) increased the risk of any coronary event by 16% (hazard ratio [HR], 1.16; 95% confidence interval [CI], 1.10-1.23; p < 0.0001), any cardiovascular event by 11% (HR, 1.11; 95% CI, 1.07-1.15; p < 0.0001), death by 23% (HR, 1.23; 95% CI, 1.14-1.34; p < 0.0001), MI by 10% (HR, 1.10; 95% CI, 1.02-1.19; p = 0.02), and stroke by 17% (HR, 1.17; 95% CI, 1.04-1.31; p = 0.01), independent of treatment effect and achieved LDL-C levels. Results were largely consistent when adjusted for medication adherence.


The authors concluded that in subjects with CAD, visit-to-visit LDL-C variability is an independent predictor of cardiovascular events.


The difference in LDL-C variability between high- and low-dose statins was significant, but the absolute differences were minimal. Importantly, just a 12 mg/dl increase in ASV in LDL-C was associated with a 16% increase in any coronary event and an increase in death by 23%. The degree to which the increase in LDL-C variability results in an increase in cardiovascular events is based on the lipid or nonlipid effects of statins cannot be gleaned from this study. The findings have important implications in several scenarios including periods of dietary and statin noncompliance, weekly or biweekly LDL apheresis, and every other day or less frequent dosing of statins and other lipid-lowering drugs.

Clinical Topics: Dyslipidemia, Prevention, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Cholesterol, LDL, Cholesterol, Coronary Artery Disease, Coronary Disease, Heptanoic Acids, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipoproteins, LDL, Medication Adherence, Mortality, Myocardial Infarction, Risk, Stroke, Primary Prevention

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