Working Paper Review Version 2 This version is not peer-reviewed

Creatine as a Candidate to Prevent Statin Myopathy

Version 1 : Received: 11 August 2019 / Approved: 13 August 2019 / Online: 13 August 2019 (04:25:33 CEST)
Version 2 : Received: 10 September 2019 / Approved: 11 September 2019 / Online: 11 September 2019 (04:43:37 CEST)

A peer-reviewed article of this Preprint also exists.

Balestrino, M.; Adriano, E. Creatine as a Candidate to Prevent Statin Myopathy. Biomolecules 2019, 9, 496. Balestrino, M.; Adriano, E. Creatine as a Candidate to Prevent Statin Myopathy. Biomolecules 2019, 9, 496.


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 may 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 adenosine triphosphate (ATP) would follow. Accordingly, ATP synthesis is decreased in statin-treated cells. In vitro, creatine supplementation prevents the opening of mitochondrial permeability transition pore 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 elder individuals. Thus, it should be trialed, under medical supervision, in patients who cannot assume statin due to the occurrence of muscular symptoms.


creatine; statin; myopathy; muscle; myalgia; prevention; treatment; pathogenesis; pathophysiology; mitochondria


Medicine and Pharmacology, Clinical Medicine

Comments (2)

Comment 1
Received: 11 September 2019
Commenter: Maurizio Balestrino
Commenter's Conflict of Interests: Author
Comment: We added to the second paragraph of the “Common hypothesis on pathogenesis” section the following text: “Specifically, several intermediates have been proposed as causes of statin-associated myopathy, including mevalonate pathway and its end products including non-sterol isoprenoids (farnesol, geranylgeraniol), heme, ubiquinone A, dolichol, squalene and more”. For better clarity and fluency, we moved after this statement, and slightly modified, the sentence that was previously preceding it. The latter now follows this added statement and reads “In fact, multiple pathophysiological mechanisms may perhaps contribute to this condition [24]”.

We added to the paragraph describing our case report the following sentence: “Although we could not derive any statistics from this single patient, results of our crossover treatment is suggestive of efficacy, and it is consistent with Shewmon and Craig’s findings”.

We expanded the fourth paragraph of the “Discussion”, that now reads “We acknowledge that further research should be done on these subjects. For example, muscle creatine in statin-induced myopathy should be measured, to possibly confirm its decrease. In fact, so far the only investigation that was carried out on this topic was done in liver cells [39]. Albeit positive (it found that atorvastatin did indeed decrease creatine content), it certainly needs confirmation in muscle cells or tissue. Furthermore, it should be noted that the fact that in statin myopathy there is a high urinary creatine/creatinine ratio [38] does not per se indicate decrease of creatine in the muscle. In theory, it might indicate either increased blood plasma creatine linked to higher excretion rate and/or lower formation and excretion of creatinine. Nevertheless, and pending future studies, the above findings suggest that creatine supplementation may be a simple way to prevent statin-induced myopathy”.

We changed the title to “Creatine as a candidate to prevent statin myopathy”.
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Comment 2
Received: 24 November 2020
The commenter has declared there is no conflict of interests.
Comment: As correctly stated above, according to research it is generally accepted that creatine is safe and produces only mild side effects (if any at all), however there are men and women who do report high blood pressure whenever they supplement with this amino acid. They've also reported it going back down whenever coming off it, you can read about such experiences here -- . Thus, medical supervision or regular checkups should definitely be taken when supplementing with creatine, in case a person is sensitive and has an adverse reaction.
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