Statins with different lipophilic indices exert distinct effects on skeletal, cardiac and vascular smooth muscle.

AIMS: Data concerning the influence of statin lipophilicity on the myotoxic and pleiotropic effects of statins is conflicting, and mechanistic head-to-head comparison studies evaluating this parameter are limited. In order to address the disparity, this mechanistic investigation aimed to assess the effects of two short-acting statins with different lipophilic indices on skeletal, cardiac and vascular smooth muscle physiology. MATERIALS AND METHODS: Young female Wistar rats were randomised to simvastatin (80 mg kg-1 day-1), pravastatin (160 mg kg-1 day-1) or control treatment groups. Changes in functional muscle performance were assessed, as well as mRNA levels of genes relating to atrophy, hypertrophy, mitochondrial function and/or oxidative stress. KEY FINDINGS: There were no significant differences in the mRNA profiles of isolated skeletal muscles amongst the treatment groups. In terms of skeleletal muscle performance, simvastatin reduced functionality but treatment with pravastatin significantly improved force production. Rodents given simvastatin demonstrated comparable myocardial integrity to the control group. Conversely, pravastatin reduced left ventricular action potential duration, diastolic stiffness and Mhc-ß expression. Pravastatin improved endothelium-dependent relaxation, particularly in muscular arteries, but this effect was absent in the simvastatin-treated rats. The responsiveness of isolated blood vessels to noradrenaline also differed between the statin groups. The findings of this study support that the effects of statins on skeletal, cardiac and vascular smooth muscle vary with their lipophilic indices. SIGNIFICANCE: The results of this work have important implications for elucidating the mechanisms responsible for the myotoxic and pleiotropic effects of statins.

Geranylgeraniol prevents statin-induced skeletal muscle fatigue without causing adverse effects in cardiac or vascular smooth muscle performance.

The administration of geranylgeranyl pyrophosphate (GGPP) (or its precursor, geranylgeraniol [GGOH]) has been shown by several in vitro studies to be capable of abrogating statin-induced myotoxicity. Nonetheless, the potential of GGPP repletion to prevent statin-associated muscle symptoms (SAMS) in vivo is yet to be investigated. Therefore, this study aimed to evaluate the ability of GGOH to prevent SAMS in rodents. Female Wistar rats (12 weeks of age) were randomised to 1 of 4 treatment groups: control, control with GGOH, simvastatin or simvastatin with GGOH. Ex vivo assessment of force production was conducted in skeletal muscles of varying fiber composition. Ex vivo left ventricular performance and blood vessel function was also assessed to determine if the administration of GGOH caused adverse changes in these parameters. Statin administration was associated with reduced force production in fast-twitch glycolytic muscle, but coadministration with GGOH completely abrogated this effect. Additionally, GGOH improved the performance of muscles not adversely affected by simvastatin (ie, those with a greater proportion of slow-twitch oxidative fibers), and increased force production in the control animals. Neither control nor statin-treated rodents given GGOH exhibited adverse changes in cardiac function. Vascular relaxation was also maintained following treatment with GGOH. The findings of this study demonstrate that GGOH can prevent statin-induced skeletal muscle fatigue in rodents without causing adverse changes in cardiovascular function. Further studies to elucidate the exact mechanisms underlying the effects observed in this investigation are warranted.

The effect of lipophilicity and dose on the frequency of statin-associated muscle symptoms: A systematic review and meta-analysis.

Addressing the factors which lead to the development of statin-associated muscle symptoms (SAMS) is vital for maintaining patient compliance with these pharmaceuticals, and thus improving patient outcomes. This study aimed to clarify the relationship between statin lipophilicity, or dose, and the frequency of adverse muscle symptoms using a systematic review of randomised controlled trials (RCTs). RCTs, including statin monotherapy and placebo groups, which reported data on muscle adverse events were identified through the PubMed and Scopus databases. Risk ratios (RRs) and 95% confidence intervals (CI) were pooled using a random-effects meta-analysis. A total of 135 RCTs were included in this review. Statin therapy was associated with a significant, but modest, increase in the risk of adverse muscle symptoms compared to placebo (RR=1.050; 95% CI=1.014-1.089; P=0.007; I2=3.291%). This significant association was primarily due to the inclusion of RCTs recruiting participants with a history of statin intolerance. Lipophilic statins had no appreciable impact on the development of SAMS compared to hydrophilic formulations. A univariate meta-regression of dose (standardised to atorvastatin dose equivalents) and the risk of musculoskeletal complaints also showed no significant association. The results obtained from this meta-analysis indicate that there is a slight increase in the risk of SAMS, especially in individuals with a history of statin intolerance. There is limited evidence to suggest that the risk of SAMS would differ between the use of lipophilic and hydrophilic statins, or high- and low-dose therapy.