We thank Dr. Timbie for the 2 corrections. All our calculations and writing were done in mmol/L, but we added the U.S. units (mg/dL) in our revision and did this incorrectly for variances (although SDs and means are correct).

Dr. Cayley points out that most of the statin trials have used a fixed dose (4S [Scandinavian Simvastatin Survival Study] is an exception) rather than monitoring-based titration or adjustment. As our work demonstrates, trials with a fixed dose allow the opportunity to assess how cholesterol values increase over time. In patients who truly have a substantial increase, a change in treatment can be considered. Inferences can then be made about monitoring-based titration or adjustment, but we do not believe practice must exactly echo the trials, which are designed for maximum power rather than optimal practice.

Like Dr. Hong and colleagues, we would like to understand the factors that could explain and reduce the variability. Some of the variation is irreducible, such as the analytic variation from the laboratory, which has a coefficient of variation of 2.7% compared with the within-person coefficient of variation of 7.8% (1). Only some of the short-term biological variation is explained by the other factors Dr. Hong and colleagues mention.

Unfortunately, we generally do not know what these factors are. In the LIPID trial analysis, this variability was minimized by both the design (run-in periods and fixed-dose therapy) and analysis methods that accounted for patients changing therapy. In clinical practice, the variability may be greater. Therefore, our results may not hold if a patient changes medication or substantially changes diet.