Table V.

Mitochondrial (mt) Effects Reported in Patients Treated with Statins^a

Study (year)	Finding	Specifics	Comments
Vladutiu et al.¹⁵⁵ (2006)	Mt pathology on biopsy in patients with statin- associated muscle symptoms.	52% of muscle biopsies (among biopsied persons with statin muscle symptoms) showed significant biochemical abnormalities in mt or fatty acid metabolism, with 31% having multiple defects.¹⁵⁵	Fraction of abnormalities that represent cause of statin vulnerability vs consequence of statin cannot be ascertained from these data (i.e. degree to which the mt pathology preceded and predisposed to symptoms on statins, vs resulted from the statins, remains unclear).
Oh et al.³⁹⁷ (2007)	Genetic impairment in coenzyme Q10 production is linked to risk of statin myopathy.	Mild common mutations in a gene involved in production of coenzyme Q10 were linked to risk of statin myopathy.³⁹⁷	Persons with rarer and more severe mutations linked to primary coenzyme Q10 deficiency, a severe condition, can have myopathy without statins.
Gambelli et al.⁴⁰⁶ (2004)	Mt pathology on biopsy in patients with statin- associated muscle symptoms.	In nine patients with “various myopathic syndromes” taking statins, muscle biopsy showed mt alterations such as COX-negative staining fibers. Findings were felt to “confirm that statins may cause muscle damage and impair oxidative metabolism.”⁴⁰⁶	Cause vs consequence ambiguity.
Meyer et al.⁴⁰⁷ (2005)	Patients on statins showed altered ³¹P-MRS spectra.	Elevated muscle phosphodiesterase was seen in ³¹P-MRS spectra of patients on statins relative to controls.⁴⁰⁷ (However, still more marked alterations were seen in one control subject – who had recently discontinued statins due to muscle symptoms.)	In the person experiencing muscle AEs, there remains cause vs consequence ambiguity.
Schick et al.⁴⁰⁸ (2007)	High-dose (lipophilic) statins significantly reduced muscle coenzyme Q10 and muscle mt DNA.	Decreased skeletal muscle mt DNA was seen in muscle biopsies of patients treated with high-dose simvastatin (80mg); this correlated with reductions in muscle ubiquinone (coenzyme Q10).⁴⁰⁸	Study involved high-dose simvastatin (80mg) vs atorvastatin (40mg) vs placebo. Effects appeared to be most marked for coenzyme Q10 reduction and mt DNA/nuclear DNA in the simvastatin group (p=0.002).
Guis et al.⁴⁰⁹ (2006)	Statin myopathy patients showed abnormal pH recovery on ³¹P-MRS.	Patients with CK elevation and muscle symptoms on statins did not show altered phosphocreatine recovery of ³¹P-MRS or mt defects on gross histology, but ³¹P-MRS did show slowed pH recovery kinetics.⁴⁰⁹ (Biopsies were not assessed by up-to-date mt testing techniques.)
Phillips et al.³¹ (2002)	Statin myopathy was associated with partially reversible mt myopathy in a double-blind, crossover, biopsy study.	In four patients with non-CK -elevating or minimally-CK -elevating muscle symptoms on statins who underwent double-blind, crossover, biopsy study, muscle biopsies showed evidence of mt dysfunction that included “abnormally increased lipid stores, fibers that did not stain for cytochrome oxidase activity, and ragged red fibers. These findings reversed in the three patients who had repeated biopsy while off statins.”³¹
Phillips et al.¹⁵⁸ (2004)	Statin use increased RER consistent with reduced lipid oxidation. Statin myopathy patients had high RER even off statins.	- Statin myotoxicity is associated with abnormal lipid oxidation.¹⁵⁸ - Statins significantly increased fasting RER in 16 normal controls (with decreased lipid oxidation) (p=0.00001).¹⁵⁸ - Persons who had had statin myopathy (and were off statins) had abnormally high fasting RER relative to controls (n=11, p=0.00001). - Post-myositis patients had a depressed anaerobic threshold (p=0.009). Patients included those with rhabdomyolysis (defined here as muscle symptoms with CK ≥ 10 × ULN) or myositis (defined here as muscle symptoms with any CK elevation).	In the post-myositis group, it is again unclear the degree to which the high RER preexisted and predisposed to statin myopathy, vs was caused by statins in the setting of statin myopathy.
Paiva et al.⁴¹⁰ (2005)	Patients on high potency simvastatin showed reduced muscle coenzyme Q10, reduced respiratory enzyme and citrate synthase activity on biopsy, and reduced mt volume.	- 48 patients (33 men, 15 women) with hyperlipidemia were randomly assigned, 16 per group, to simvastatin 80mg, atorvastatin 40mg, or placebo for 8 weeks with muscle biopsy at baseline and end.⁴¹⁰ - The ratio of plasma lathosterol: cholesterol decreased 66% in both statin groups. Muscle campesterol increased similarly in the two statin groups (simvastatin 21 ± 7 to 41 ± 27nmol/g; atorvastatin 23 ± 9 to 40 ± 19nmol/g, p=0.005). Muscle coenzyme Q10 dropped significantly in the simvastatin group only (40 ± 14 to 26 ± 8nmol/g, p=0.03). - Respiratory chain enzyme and citrate synthase activities dropped significantly in those with marked reductions in muscle coenzyme Q10 on simvastatin 80mg, compared with ‘matched’ patients on atorvastatin 40mg or placebo (n=6 in each group).	Larger sample may clarify if qualitatively similar effects occur in a subset of patients on atorvastatin as well.
De Pinieux et al.²² (1996)	Statins (but not fibrates) significantly lowered coenzyme Q10 and increased the lactate : pyruvate ratio, used as a marker of mt function.	80 hyperlipidemic persons on statins (n=40), on fibrates (n=20), or untreated (n=20), and 20 healthy controls were compared.²² Statin use was linked to significantly higher lactate: pyruvate ratios than in untreated subjects (p<0.05) or healthy controls (p<0.001). Coenzyme Q10 was lower in statin- treated than in untreated patients (0.75 ± 0.04mg/L vs 0.95 ± 0.09mg/L, p<0.05).

AE = adverse effect; CK = creatine kinase; COX = cytochrome C oxidase; MRS = magnetic resonance spectroscopy; RER = respiratory exchange ratio; ULN = upper limit of normal.

Either in settings of statin use or of statin AEs.