title: Atorvastatin metabolite measurements as a diagnostic tool for statin-induced myopathy.
abstract: BACKGROUND
  Myopathic complaints are common in the general population and are more frequent with increasing age. When myopathic symptoms arise in a patient treated with a HMG-CoA reductase inhibitor (statin), it is always a question of whether the symptoms are due to statin-induced myopathy (SIM) or not (non-SIM). Diagnosis of SIM is not as straightforward as previously thought, because the most commonly used biomarker, serum creatine kinase, shows low specificity and selectivity, except in serious cases of rhabdomyolysis. There is a definite need for a novel biomarker for SIM.
  
  
  OBJECTIVE
  Based on a previous study reporting an altered metabolic profile with increased systemic exposure to the suspected muscle-toxic metabolite atorvastatin lactone in patients with SIM compared with healthy controls, this study aimed to explore the use of atorvastatin metabolite measurements to diagnose muscular complaints during statin treatment as being either SIM or non-SIM. PATIENTS, SETTING, AND STUDY DESIGN: Fifty-three patients with self-reported myopathic symptoms during atorvastatin treatment were recruited from our outpatient clinic. The symptoms were clinically evaluated as being SIM or non-SIM, on the basis of atorvastatin re-challenge testing. Atorvastatin and its metabolites were measured at steady state in all patients and compared with the clinical evaluation to see if this could predict the outcome and hence be suitable as a diagnostic tool for SIM.
  
  
  METHODS
  This was an exploratory study to investigate the proportion of patients correctly diagnosed by different metabolite cut-off ratios.
  
  
  RESULTS
  With a cut-off ratio set at 1.1 for the atorvastatin lactone to atorvastatin acid ratio, 15 of 28 SIM patients (sensitivity of 54%) and 20 of 24 non-SIM patients (specificity of 83%) were correctly diagnosed. This corresponds to a positive predictive value of 79% and a negative predictive value of 61% (p = 0.006).
  
  
  CONCLUSIONS
  The present study confirms an altered metabolic pattern of atorvastatin in patients with SIM and substantiates a central role of the lactone forms of statins in future investigations of statin myotoxicity. The atorvastatin lactone to acid ratio seems to be a valuable supportive diagnostic tool with high specificity and moderate sensitivity, adding to ordinary clinical evaluations when diagnosing SIM.
authors.affiliation: School of Pharmacy, University of Oslo, Oslo, Norway.
authors.forename: Ine B
authors.initials: IB
authors.lastname: Skottheim
authors.forename: Martin P
authors.initials: MP
authors.lastname: Bogsrud
authors.forename: Monica
authors.initials: M
authors.lastname: Hermann
authors.forename: Kjetil
authors.initials: K
authors.lastname: Retterstøl
authors.forename: Anders
authors.initials: A
authors.lastname: Åsberg
mesh_terms: D000328:Adult; D000368:Aged; D000069059:Atorvastatin; D015415:Biomarkers / Q000097:blood; D003402:Creatine Kinase / Q000097:blood; D005260:Female; D006538:Heptanoic Acids / Q000009:adverse effects* / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology; D011758:Pyrroles / Q000009:adverse effects* / Q000378:metabolism*; D012206:Rhabdomyolysis / Q000139:chemically induced / Q000175:diagnosis / Q000453:epidemiology; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin; D003402:Creatine Kinase