Creatine as a Candidate to Prevent Statin Myopathy

Abstract

Statins prevent cardiovascular diseases, yet their use is limited by the muscle disturbances they cause. Rarely, statin-induced myopathy is autoimmune, but more commonly it is due to direct muscle toxicity. Available evidence suggests that statin-induced creatine deficiency might be a major cause of this toxicity, and that creatine supplementation prevents it. Statins inhibit guanidinoacetate methyl transferase (GAMT), the last enzyme in the synthesis of creatine; thus, they decrease its intracellular content. Such decreased content could cause mitochondrial impairment, since creatine is the final acceptor of the phosphate group of adenosine triphosphate (ATP) at the end of mitochondrial oxidative phosphorylation. Decreased cellular synthesis of ATP would follow. Accordingly, ATP synthesis is decreased in statin-treated cells. In vitro, creatine supplementation prevents the opening of the mitochondrial permeability transition pore that is caused by statins. Clinically, creatine administration prevents statin myopathy in statin-intolerant patients. Additional research is warranted to hopefully confirm these findings. However, creatine is widely used by athletes with no adverse events, and has demonstrated to be safe even in double-blind, placebo-controlled trials of elderly individuals. Thus, it should be trialed, under medical supervision, in patients who cannot assume statin due to the occurrence of muscular symptoms.

Keywords: creatine; mitochondria; muscle; myalgia; myopathy; pathogenesis; pathophysiology; prevention; statin; treatment.

Figure 1

The “ATP shuttle” role of the creatine-phosphocreatine system. In the mitochondrion, oxidative phosphorylation leads to the production of ATP from ADP. The former should travel a considerable length into the cytoplasm to reach the peripheral ATPases enzymes that it must fuel. However, ATP is a rather large and electrically charged molecule; thus, such diffusion would not be easy. Therefore, creatine takes up the phosphate of ATP, transforming itself into phosphocreatine. Since phosphocreatine is a smaller molecule than ATP, it diffuses more easily through the cytoplasm, reaching the peripheral ATPases. There it donates its phosphate group to ADP, providing ATP. By doing so, phosphocreatine reverts to creatine and migrates along its diffusion gradient back to the mitochondrion to start the cycle again [48]. Abbreviations: ATP = adenosine triphosphate; ADP = adenosine diphosphate; Cr = creatine; PCr = phosphocreatine.

Figure 2

Structure of lovastatin in (A) lactone form and (B) open hydroxy acid form. After their administration in vivo, all statins exist in both forms, which are at an equilibrium between themselves [63]. Figure reprinted from Patil et al., with permission [64].

Figure 3

Myopathy score during the various treatments with creatine and/or statin. The graph was designed by us using the data reported by Shewmon and Craig [38]. Statistical findings are for Wilcoxon matched-pairs signed-rank test (2-tailed) comparing each phase with baseline, as reported by Shewmon and Craig; n.s. = not significant. See text for more details.

Figure 4

Serum levels of creatine kinase (CK) and muscle pain in the patient we treated with creatine supplementation. Muscle pain occurred and CK levels rose to abnormal levels when statins were prescribed, but not when the statin was prescribed together with creatine. Reprinted from reference [68], with permission of the publisher.