Low-density lipoprotein cholesterol increased significantly after short-term discontinuation of atorvastatin, but did not correlate with plasma drug concentrations
Authors: Sverre E , Piourevonas J , Kristiansen O , Peersen K , Lauritzen T , Husebye E , Fagerland M , Vethe NT , Munkhaugen J 
Published: May 2022

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): The Dam foundation

Introduction
Statin non-adherence remains a prevalent challenge in cardiovascular disease prevention and robust methods to monitor adherence are needed. Large variations in low-density-lipoprotein cholesterol (LDL-C) response to a given type and dose of statin have been reported. The LDL-C response to short-term discontinuation of statins is not well defined. Moreover, the relationship between the blood concentrations of statin metabolites and LDL-C, and how clinical factors interact, are unknown.

Purpose
To determine changes in LDL-C at an individual and group level during four-day discontinuation of atorvastatin, and to investigate whether clinical factors and atorvastatin metabolites concentration correlate with changes in LDL-C.

Methods
This clinical pharmacokinetic adherence study conducted in 2021, included 60 adult participants treated with atorvastatin 20 mg (n=20), 40 mg (n=20) or 80 mg (n=20). The participants were instructed to take atorvastatin daily between 07 and 10 am the week before study start, to ensure steady state drug concentrations. The last dose of atorvastatin was taken 24 hours prior to the first blood sampling (day zero). Atorvastatin doses were omitted until after blood sampling on the fourth day. The concentrations of atorvastatin metabolites (acid and lactone forms, including 2-OH- and 4-OH metabolite) were measured by a liquid chromatography–tandem mass spectrometry assay. Paired-samples T-tests, Spearman rank correlations and linear regression analyses were performed with SPSS.

Results
Mean age was 65 (SD 11) years, 18 (30%) were female, 45 (75%) had cardiovascular disease and 11 (18%) had diabetes mellitus. Mean LDL-C at steady state on day zero was 1.9 (SD 0.6) mmol/L. LDL-C increased on average by 0.5 (SD 0.3) mmol/L (30%) from day zero to day four, during the period with atorvastatin discontinuation. The increase of LDL-C was significant already after the first omitted dose (day one) (Figure 1). LDL-C increased from day zero to day four in 78 out of the 80 patients (97.5%). Higher Body Mass Index was significantly associated with lager increase in LDL-C during the four-day discontinuation (B 0.02, 95% CI 0.01 to 0.04, p=0.028), whereas age, sex, kidney function, cardiovascular disease and diabetes were not. Changes in atorvastatin plus metabolites concentration from day zero to day four were not associated with changes in LDL-C during discontinuation (Figure 2). This also applied if we assessed the individual atorvastatin metabolites.

Conclusion
Atorvastatin discontinuation for only four days resulted in a statistically significant 30% increase of LDL-C. Atorvastatin pharmacokinetics did not correlate with change in LDL-C during the discontinuation. Even short-term non-adherence may have unfavourable consequences, and deserves further attention.