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

## TL;DR

Stopping atorvastatin for four days causes a significant rise in LDL cholesterol, linked to metabolite half-lives.

## Contribution

The study reveals a significant LDL-C increase after short-term atorvastatin discontinuation and its correlation with metabolite half-lives.

## Key findings

- LDL-C increased by 27% after four days of atorvastatin discontinuation.
- LDL-C rose significantly within 48 hours of the last dose.
- Hydroxylated metabolite half-lives correlated moderately with LDL-C increases.

## Abstract

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.

Created in BioRender. Munkhaugen, J. (2025) https://BioRender.com/g40l253.