Clarifying the role of pharmacological factors in the pathogenesis of statin-associated muscle symptoms and the ability of geranylgeranyl pyrophosphate to prevent statin-induced muscle fatigue

Background: The onset of statin-associated muscle symptoms (SAMS) can reduce quality of life in affected individuals, and also presents a significant obstacle for maintaining compliance with these pharmaceuticals. More effective strategies for managing the various clinical manifestations of SAMS are required; however, identifying such therapies has been complicated by the multifaceted and variable aetiology of statin-induced myotoxicity. Much ambiguity remains surrounding the molecular mechanisms underlying the different forms of SAMS, as well as the role of pharmacological factors in the pathogenesis of these conditions. It has been suggested that the co-administration of geranylgeranyl pyrophosphate (GGPP) with statins may prevent myotoxic effects; however, this is yet to be thoroughly investigated in vivo. Accordingly, the aim of this thesis was to clarify the role of statin lipophilicity and dose in the pathogenesis of SAMS, as well as to determine the feasibility of GGPP repletion to prevent statin-induced myotoxicity in vivo. Methods: In order to meet these objectives, a systematic-review and meta-analysis was conducted, as well as a series of rodent-based studies. Data for the meta-analysis was obtained from 135 randomised controlled trials which reported information on SAMS. The animal studies included a series of functional, molecular and biochemical analyses aimed at assessing the impact of statin and/or GGPP administration (in the form of geranylgeraniol) on skeletal muscle integrity. Additionally, cardiac and vascular smooth muscle performance was also assessed to: (i) determine if these parameters were significantly altered by the presence of SAMS and; (ii) establish whether GGPP repletion was associated with adverse changes in these tissues. Results: The systematic review and meta-analysis found that neither statin lipophilicity nor dose had a significant influence on the frequency of SAMS in randomised controlled trials. Conversely, the results of the rodent-based studies demonstrated that treatment with a high-dose lipophilic statin was associated with greater myotoxic effects compared to low-dose or hydrophilic formulations. This work also identified that the molecular mechanisms which underlie milder forms of SAMS differ significantly from the more severe manifestations. Additionally, it was observed that GGPP administration (in the form of geranylgeraniol) was able to prevent the myotoxic effects of statins without causing adverse changes in cardiovascular performance. Conclusion: The findings of this study suggest that both lipophilicity and dose can influence the myotoxic potential of statins; however, the significance of this effect may be altered in the presence of other risk factors for SAMS. This work also demonstrates that GGPP repletion is a feasible intervention for preventing statin-induced skeletal muscle damage in vivo. In turn, the findings of this project have significant implications for elucidating the pathogenesis, and potential treatment, of SAMS.