Abstract 1495: Serum Creatine/Creatinine Ratio Elevation and Statin Myalgia
The major limiting factor of the statin class of cholesterol-lowering drugs is muscle toxicity, for which a useful biomarker and a clear mechanism of pathogenesis have yet to be elucidated. An elevated ratio of creatine/creatinine (CR/CRN) in urine has been used as a marker of myopathy from steroid therapy, a disease in which lytic markers such as CPK are not elevated. We reasoned that CR/CRN in serum might be similarly used to study the muscle toxicity from statins. Spectrophotometric assays were used to determine serum concentrations of creatine and its nonenzymatic breakdown product, creatinine, using blood samples drawn between 8–9AM. We studied baseline serum CR/CRN values of subjects who were previously intolerant (INTOL) to 3 different statins (myalgia confirmed on rechallenge each time), comparing them to subjects who tolerated (TOL) the first statin given to them without discomfort. The mean +/−SD of CR/CRN for INTOL was significantly higher than that for TOL (0.845 +/− 0.203, n=10, vs. 0.282 +/− 0.167, n=11, p < 0.0001). We also studied subjects who were undergoing rechallenge with a statin after having experienced myalgia on initial treatment. We measured serum CR/CRN after the resolution of myalgia, and again when moderate to marked myalgia had returned. We found that the CR/CRN was 48.7 +/− 32.1% higher during myalgia than at baseline (p=0.032 by paired t-test, n=5). In all cases, CR/CRN elevations during myalgia were marked by decreases in serum creatinine concentrations, with negligible differences in serum creatine levels, suggesting the presence of intracellular creatine deficiency. Disruption of the transmembrane electrochemical gradient of Cl− has been described with cholesterol reduction and statin use, potentially impairing Na+-K+-Ca2+ ATPase activities. We propose that these pathophysiologic effects may impair function of the Na+- and Cl− dependent creatine transporter protein, resulting in myalgia from ineffective ATP buffering by the creatine/phosphorylcreatine/CPK phosphagen system. In summary, serum CR/CRN may be useful as a diagnostic tool for predicting and monitoring statin muscle toxicity. In addition, our findings suggest that oral creatine supplementation may help alleviate muscle toxicity symptoms from statins.