Clinical and pharmacological characteristics in plasma and mononuclear blood cells in patients with coronary heart disease and low statin tolerance
Authors: Lauritzen T , John Munkhaugen JM , Kari Peersen KP , Elise Sverre ES , Oscar Kristiansen OK , Elena Prunes Jensen EPJ , Stein Bergan SB , Einar Husebye EH , Nils Tore Vethe NTV 
Published: May 2022

Abstract

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

Background
Statin-associated muscle symptoms (SAMS) cover a broader range of clinical presentations, with normal or mildly elevated creatine kinase (CK) in blood, and is a prevalent challenge in clinical practice. Our understanding of the pathophysiology of SAMS remains largely unknown.

Purpose
To gain new knowledge on the molecular effects of atorvastatin in plasma and blood cells in patients with coronary heart disease (CHD) and SAMS, and to identify potential diagnostic biomarkers for statin-dependent SAMS.

Methods
In 2019, 71 consecutively recruited CHD patients with self-perceived SAMS were randomised to 7-weeks double-blinded treatment with atorvastatin 40 mg/day and placebo in a crossover design. The primary outcome was individual mean difference in muscle symptom intensity between treatment periods, measured weekly with a Visual Analogue Scale (VAS) (0= no to 10=maximal symptoms). Twenty patients were categorised as having statin-dependent SAMS and the remaining as non-SAMS. During trial and post-trial follow-up period, a subgroup of statin-dependent SAMS, who did not tolerate statins (N=7) or only rosuvastatin 5mg/day (N=2) was identified. Atorvastatin metabolites in plasma and peripheral blood mononuclear cells (PBMC) were measured with liquid chromatography tandem mass spectrometry in blood drawn two hours after tablet intake at the last day of the atorvastatin treatment period. Statistical analyses were performed with SPSS.

Results
Clinical and pharmacological characteristics in patients with low statin-tolerance (N=9) and those without (N=62) are summarised in Figure 1. The reduction in LDL cholesterol (LDL-C) from the placebo period to the atorvastatin period was significantly lower in the group with low statin tolerance, despite confirmed adherence to allocated treatment. The ratio between the sum of all atorvastatin- lactones and acids (SumLactones/SumAcids) was significantly higher in the group with low statin tolerance both in plasma and PBMC analyses compared to those who tolerated statins. The atorvastatin lactone and acid ratio (AL/AA) was borderline significant in both plasma and PBMC. ROC-analyses of these four variables are displayed in Figure 2. Areas under the curves (AUCs) are 0.71 for the sumLactones/sumAcids both in plasma and PBMC, and 0.69 for the AL/AS in plasma and PBMC. There were no significant differences between the groups regarding age, gender or known pharmacogenetic variants (CYP3A and SLCO1B1) or in the differences in creatine kinase (CK) level between the atorvastatin and placebo treatment periods.

Conclusions
The ratio between atorvastatin lactones and acids in plasma and in mononuclear blood cells is associated with low statin tolerance in patients with CHD. Excess lactone relative to acid metabolites may be involved in the pathophysiology of SAMS. Future studies in muscle tissue may further elucidate the relationship between SAMS and atorvastatin metabolites and other biomarkers in these patients.