**4. Muscle sensitivity to statins**

It is well known that about 10% of patients undergoing statin treatment develop mild myopathic symptoms such as weakness, muscle pain, exercise intolerance, and other symptoms that are usually with normal or minimally elevated creatine kinase (CK) serum levels [149, 150]. Moreover, myositis, defined as muscle symptoms associated with increased CK, is usually present [151, 152]. Rhabdomyolysis, the most severe adverse effect of statins, is a very rare condition affecting 1.6/100,000 patients-years. It may result in acute renal failure and disseminated intravascular coagulation, leading to death. This condition is frequently related to drug interactions and occurs with CK levels 10-fold higher than the normal limit and elevated levels of creatinine [153, 154]. Increased intracellular lipid stores, cytochrome oxidase-negative myofibers, ragged red fibers, and subsarcolemmal accumulation of mitochondria were found in patients with muscle symptoms during statin therapy [155, 156]. Schick and colleagues also observed reduced mitochondrial DNA levels in patients treated with simvastatin [157]. Muscle-associated statin toxicity seems to be more severe with increasing lipophilicity, whereas more hydrophilic statins exert only mild or no toxicity [133, 153]. The myotoxic effect is attributed to their ability to penetrate and accumulate in cell membranes and alter their structural conformation [158–160]. On the other hand, high statin sensitivity may also be related to genetic factors; for instance, the activity of specific liver transporters may be impaired, thus reducing statins hepatic uptake and increasing its plasma concentrations that may potentially affect muscles [161–163].

**5. Statins toxicity to liver**

**6. Statins and new onset of diabetes**

Although rare, the main liver injury studies have reported statins toxicity alone [173–176] or in combination with other drugs with variable patterns of injury [177–181]. Some cases exhibited autoimmune features [180, 182, 183] and a range of latencies to onset [184] and progression was also observed [182, 185]. Liver adverse symptoms are unspecific and most patients remain asymptomatic [186]. A 3-fold increase in serum aspartate (AST) and alanine (ALT) aminotransferases activities have been described in less than 1% of patients receiving starting and intermediate statins doses [187–191] and this alteration may be accompanied by bilirubin elevation [192]. Two factors are frequently related to the hepatotoxic effects of statins: (a) the lipophilicity of these medicines and (b) alterations in cytochrome P450 system [193–195]. Accordingly, lipophilic statins (atorvastatin and simvastatin) are associated with more than 130 cases of liver injury, and a few cases progress to liver transplantation and death [173, 174, 178]. Rare cases of portal inflammation or fibrosis and mild necrosis were also described in patients undergoing lovastatin treatment [196] or atorvastatin treatment [197]. On the other hand, hydrophilic statins are minimally metabolized by the cytochrome P450 pathway [193–195] and are generally less toxic [109, 198]. A multicenter report also showed that pravastatin was well-tolerated in patients with compensated chronic liver disease [199]. Our group also attributes statin-induced liver toxicity to mitochondrial dysfunction associated with oxidative stress and MPT [193].

Mitochondrial Oxidative Stress and Calcium-Dependent Permeability Transition are Key Players…

http://dx.doi.org/10.5772/intechopen.71610

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Recent studies suggest that chronic use of statins is associated with risk of developing type 2 diabetes [200–202]. Meta-analyses of large-scale statin trials support the concept of the diabetogenic effect of statins, but the precise mechanisms have not yet been identified [203, 204]. We have recently revealed diabetes-related mechanisms induced by statin treatment in a familial hypercholesterolemia animal model, the *LDLr−/−*. We demonstrated that pravastatintreated *LDLr−/−* mice exhibit marked reductions of insulinemia and of glucose-stimulated insulin secretion by isolated pancreatic islets. These effects were associated with increased oxidative stress and apoptosis [205] and were counteracted by co-treatment with CoQ10 (Lorza-Gil et al., unpublished data). Therefore, we have proposed that pancreatic toxic effects of pravastatin could be caused by statin inhibition of CoQ10 biosynthesis. On the other hand, we and others have hypothesized that insulin signaling in their target tissues (such as muscle) could also be impaired by chronic statin treatment. However, studies relating statins therapy and insulin sensitivity are controversial [206–208]. A meta-analysis by Baker and colleagues shows that while pravastatin improved insulin sensitivity, atorvastatin, simvastatin, and rosuvastatin worsened it [209]. Experimental studies suggest that atorvastatin leads to reduced expression of GLUT4 in adipocytes *in vivo* and *in vitro* [210] and that simvastatin decreases IGF-1 signaling (pAKT, pERK) in muscle cells [211]. Kain et al. [212] showed that myotubes treated with simvastatin and atorvastatin presented impaired insulin signaling pathway and glucose uptake. We have evidence that long-term pravastatin treatment of hypercholesterolemic mice also induces

Skeletal muscles are highly heterogeneous and present distinct fiber types classified as I or II and their respective subtype spectrum as determined by the myosin heavy chain isoforms. Type I and II fibers present relatively distinct metabolic, contractile, and motor properties in addition to antioxidant defense capacity. Thus, type I fibers appear red due to high myoglobin content, extensive mitochondrial content, and oxidative capacity, whereas type II fibers have relatively low myoglobin and mitochondrial content that depends mostly on glycolytic activity [164, 165]. In this regard, our group observed that respiratory rates were inhibited in the presence of Ca2+ in permeabilized plantaris muscle (predominantly type II fibers) in *LDLr−/−* mice chronically treated with pravastatin and catalase activity increased. In contrast, no alterations were observed in soleus muscle (predominantly type I fibers) [166]. Similarly, previous studies reported a distinct sensitivity of different muscle fiber types to lovastatin [162]. After 10 days of lovastatin administration, rat gastrocnemius muscles showed organelle degeneration, microvacuolization, and 20–50% necrosis, whereas soleus muscle was spared, suggesting that type II fibers are more vulnerable to lovastatininduced myopathy [167]. In line with this finding, Westwood and colleagues characterized time-dependent muscle necrosis triggered by simvastatin or cerivastatin in rats after 10 days of treatment. The authors demonstrated that glycolytic fibers were more prone to necrosis than oxidative fibers, which in turn were consistently spared even when myotoxicity was severe. Since these fibers present distinct metabolism and MPT may precede necrosis, it is conceivable that mitochondria exert a central role in this process. In fact, it was observed that the first subcellular alterations were found in mitochondria of type II fibers, characterized by vacuolization as well as myeloid and vesicular body accumulation in sarcolemma areas [168]. Later, the same group performed a similar study using rosuvastatin in rats. Although a much higher statin dose was required to achieve muscle necrosis in comparison to the earlier study, the same pattern of muscle damage was observed and the soleus muscle remained unaffected [169]. Specific soleus-insensitivity to statin toxicity has also been demonstrated by other groups. Schaefer and coworkers demonstrated necrosis and inflammation in muscles with predominance of type II fibers in rats after 15 days of cerivastatin administration. Sarcomere disruption and altered mitochondria was also found in degenerated fibers, while these alterations were not found in type I fibers [170]. Similarly, cerivastatin-induced degeneration was evident in several muscles but not in the soleus muscle of female rats after the same treatment time (15 days). After 15 days of treadmill exercises, the severity of muscle damage had increased, but the soleus remained unaltered. Degenerated mitochondria were also observed with no changes in contractile elements such as endoplasmic reticulum and other subcellular compartments [171]. Although the role of mitochondria in myotoxicity in type II fibers is well established, there is no consensus as to whether this involvement precedes myofiber degeneration, thus justifying further studies to clarify this matter [170, 171]. In addition, MPT is associated with apoptosis or necrosis in several diseases [172] and is probably an important statin-induced event in muscle necrosis.
