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maandag 20 februari 2012

Statin Adverse Effects: Evidence for a Mitochondrial Mechanism

Statin Adverse Effects: A Review of the Literature and Evidence for a Mitochondrial Mechanism
In the case of statins, a potential basis for opposing effects occurring in muscle and in other organs can be identified. Evidence supports the proposition that antioxidant effects of statins underlie (or contribute to) many fundamental statin benefits – including benefits to flow and oxygen delivery46-48 and inflammation.49, 50 These effects may participate in improved walking distance in patients on statins, including benefits to muscle/walking in persons with and without peripheral artery disease.29 Yet a subset of people reproducibly exhibit increases in markers of oxidation on statins,51 and the occurrence of this increase has been tied to muscle pain on statins.52, 53
A range of cases have now been reported in which statin use has “uncovered” previously clinically silent or clinically tolerated conditions, ranging from McArdle disease159, 160 to myotonic dystrophy159 to acid maltase deficiency161 to possible Kennedy disease.159 Statins have also exacerbated known muscle conditions, such as myasthenia gravis.78 In the case of mitochondrial myopathies, the relative degree to which statins have unmasked vs induced disease may not always be clear.159, 162

Several widely used statins – atorvastatin, simvastatin, and lovastatin (and previously cerivastatin, now off the market) – are metabolized by the cytochrome P450 (CYP)3A4 pathway.318
While a medley of potential mechanisms may cause or contribute to statin AEs (and these merit more full review in another venue), mitochondrial mechanisms have been repeatedly implicated in muscle AEs. Mitochondrial defects predispose to problems on statins (as shown in the second to last entry of Table IV, ‘Genetic mutations associated with mitochondrial dysfunction’). Additionally, statins predispose to mitochondrial defects (Table V,22 31, 32, 112, 155, 158, 162, 397, 406-414) – in all users and, to a greater degree, in vulnerable individuals. Dose-dependent reductions in coenzyme Q1020-22 can reduce cell energy, promote oxidation,362, 415 promote apoptosis, and unmask silent mitochondrial defects.23-25, 362, 415-418 The mevalonate pathway, which statins inhibit, also produces heme-A, which has it own central involvement in mitochondrial electron transport.419
 For instance, mitochondrial encephalomyopathy resulting from heritable coenzyme Q10 deficiency classically produces fatigue, muscle symptoms, and cognitive problems,440 although the cases referred for analysis are often relatively severe.429, 441 Gastrointestinal26 and neurological symptoms,432, 442 psychiatric symptoms,443-446 sleep problems,444, 447 glucose elevations,182 and a range of other symptoms reported on statins also arise in mitochondrial dysfunction.379, 448-457
Thus, in an analysis of data, presented in the Australian Adverse Drug Reaction Bulletin, it was noted that “Statin-associated peripheral neuropathy may persist for months or years after withdrawal of the statin… In two ADRAC (Adverse Drug Reactions Advisory Committee) cases of persistent peripheral neuropathy, motor and sensory conduction tests showed minimal recovery 4 and 12 months, respectively, after discontinuation of simvastatin, despite clinical improvement.”561

As reviewed here, AEs on statins may signal a mitochondrial vulnerability, which may alter or perhaps even reverse an otherwise favorable impact of statins on cell energetics. And AEs may signal occurrence of a net prooxidant rather than antioxidant effect of statins53 with possible unfavorable implications for a range of statins' proposed pleiotropic effects.892

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