Low‐Density Lipoprotein Cholesterol Increases Significantly During Brief Discontinuation of Atorvastatin and Correlates With Metabolite Half‐Lives

Variability in low-density lipoprotein cholesterol (LDL-C) has emerged as a potential independent cardiovascular risk factor, but the impact of short-term discontinuation of statins on LDL-C remains to be defined. Furthermore, the relationship between individual statin metabolites and changes in LDL-C has not yet been examined. The present study aimed to investigate changes in LDL-C concentrations during a four-day discontinuation of atorvastatin therapy and to examine correlations between the half-lives of atorvastatin metabolites and LDL-C concentrations. This pharmacokinetic intervention study included 60 adults with confirmed adherence to atorvastatin, using doses of 20 mg (N = 20), 40 mg (N = 20), or 80 mg (N = 20) at study start. Atorvastatin was then discontinued, and blood samples were collected from day zero to day four. We assessed daily concentrations of LDL-C and of atorvastatin with its metabolites by liquid chromatography-tandem mass spectrometry. The mean (SD) LDL-C at baseline was 1.84 (0.6) mmol/L. LDL-C increased on average by 0.50 mmol/L (27%) from day zero to day four. The increase in LDL-C was significant already 48 h after the last statin intake and was affected by individual variation in baseline concentrations and the slope of the daily increase. A moderate correlation was found between differences in LDL-C concentrations and the half-lives of hydroxylated atorvastatin metabolites. In conclusion, 4 days without atorvastatin resulted in an almost 30% increase in LDL-C concentrations, and the increase was significant already after the first omitted dose. The half-lives of hydroxylated atorvastatin metabolites showed a moderate correlation with the increase in LDL-C concentrations.