Atorvastatin lactone/acid ratios are promising biomarkers for statin dependent muscular side effects in patients with coronary heart disease
Authors: Lauritzen T , Munkhaugen J M , Peersen K P , Kristiansen O K , Sverre E S , Andersen A M A , Jensen E P J , Bergan S B , Husebye E H , Vethe N T V 
Published: May 2023

Abstract

Funding Acknowledgements
Type of funding sources: Public hospital(s). Main funding source(s): Vestre Viken Hospital Trust.

Background
In clinical practice, it is challenging and time-consuming to assess whether self-perceived statin associated muscle symptoms (SAMS) are caused by the statin or not, and diagnostic biomarkers are therefore requested [1]. Atorvastatin (ATV) metabolites, especially the lactones, have been associated with statin dependent muscular side effects [2, 3].

Purpose
To assess ATV metabolites as potential diagnostic biomarkers for statin dependent muscular side effects in skeletal muscle tissue and correspondingly in blood plasma among patients with coronary heart disease (CHD).

Methods
In 2020, an open biomarker follow-up study included 26 of 71 CHD patients with self-perceived SAMS who had participated in a randomised double-blinded crossover trial (ATV 40 mg/day and matched placebo) in 2019. Twelve participants reported significantly more symptoms during blinded treatment with ATV than during placebo, whereas the remaining 14 patients reported no differences in muscle symptoms between the treatment periods. In the biomarker study, all participants received open treatment with ATV 40 mg/day for seven weeks followed by no statins for eight weeks. Muscle biopsies were collected from the vastus lateralis of the quadriceps muscle after the ATV treatment period (n=26) and after the no-statin period (n=23). Blood was collected both pre-dose, at the time of biopsy (T0) and one hour after statin intake (T1). ATV and its five major metabolites were measured in muscle homogenate and blood plasma with liquid chromatography tandem mass spectrometry. A subgroup of four patients had histological signs of statin dependent muscle cell damage and three paitent did not tolerate any statins (n=2) or only pravastatin 20mg/day (n=1). These seven patients were categorised as having statin dependent muscular side effects. Mann-Whitney test and ROC-analyses were performed with SPSS.

Results
The lactone/acid ratios (ATV lactone/acid, 2OH-ATV lactone/acid, 4OH-ATV lactone/acid, sum lactones/sum acids) in muscle were all numerically higher in the seven patients than the rest. A similar pattern was found for plasma ratios at T0 and T1. The 2OH-ATV ratio and the sum ATV ratio in muscle were significantly different (p= 0.008 and p=0.022) between those with and without statin dependent side effects. The areas under the ROC curve (AUC) were 0.84 and 0.82, with sensitivity of 71% and 67%, and specificity of 90% and 94% (Table 1 and Figure 1). In plasma, the sum ATV ratio at T0 and T1 and the ATV lactone/acid ratio at T1 appeared as the best discriminators: with AUCs ranging from 0.74 to 0.83 and sensitivity and specificity estimates at 86% and 74%, respectively.

Conclusions
ATV lactone/acid ratios, measured in blood plasma one hour after atorvastatin intake, appear as promising biomarkers for statin dependent muscular side effects. Our study provides candidate cut-off values that should be pursued further for the determination of diagnostic sensitivity and specificity.