Simvastatin Effects on Skeletal Muscle

Larsen, Steen; Stride, Nis; Hey-Mogensen, Martin; Hansen, Christina; Bang, Lia E.; Bundgaard, Henning; Nielsen, Lars Bo; Helge, Jørn Wulff; Dela, Flemming

doi:10.1016/j.jacc.2012.09.036

Cited by 151 publications

(66 citation statements)

References 44 publications

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“…Different studies (longitudinal and crosssectional) have reported an impaired mitochondrial function after statin therapy [53,54] , which may compromise the OXPHOS capacity of the skeletal muscle. This would, in turn, further cause exercise intolerance.…”

Section: Lipid-lowering Agents (Statins)mentioning

confidence: 99%

“…This would, in turn, further cause exercise intolerance. It has been suggested [54] that the culprit behind the impaired mitochondrial function, maybe a reduced coenzyme Q10 content in the skeletal muscle ( Figure 1). It must be mentioned that not all studies have found a negative effect of statin therapy in combination with exercise [55] .…”

Section: Lipid-lowering Agents (Statins)mentioning

confidence: 99%

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Effects of exercise training on mitochondrial function in patients with type 2 diabetes

Larsen

Skaaby

Helge

et al. 2014

WJD

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Core tip: It is well described that exercise interventions improves insulin sensitivity and maximal oxygen uptake in patients with type 2 diabetes as well as in control subjects. When it comes to adaptations in mitochondrial function after an exercise intervention the literature is more sparse especially in patients with type 2 diabetes. Furthermore the medication that patients with type 2 diabetes are using, are often not described well in the papers, and it is known that the different medication (statins and antihypertensive agents) have a major effect on mitochondrial function and insulin sensitivity.Larsen S, Skaaby S, Helge JW, Dela F. Effects of exercise training on mitochondrial function in patients with type 2 diabetes.

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Section: Lipid-lowering Agents (Statins)mentioning

confidence: 99%

Section: Lipid-lowering Agents (Statins)mentioning

confidence: 99%

Effects of exercise training on mitochondrial function in patients with type 2 diabetes

Larsen

Skaaby

Helge

et al. 2014

WJD

Self Cite

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“…This has been reported to manifest as decreased TCA enzyme content (7), impaired electron transport involving both complexes I and II (8, 28), increased lactate to pyruvate ratios (29), impaired skeletal muscle mitochondrial calcium signaling (28, 30), and mitochondrial apoptosis (2). Evidence for a statin-induced reduction in human muscle CoQ content are controversial with tissue levels reportedly increased (31), decreased (7), possibly decreased (9), or unchanged (32).…”

Section: Discussionmentioning

confidence: 99%

Evidence for metabolic aberrations in asymptomatic persons with type 2 diabetes after initiation of simvastatin therapy

Suneja

Fox

Fink

et al. 2015

Translational Research

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HMG-CoA reductase inhibitors (statins) prevent vascular events and are widely prescribed, particularly in persons with type 2 diabetes. However, intolerability due to myopathic symptoms often limits their use. We investigated the effects of simvastatin on parameters of mitochondrial function and muscle gene expression in 11 subjects with type 2 diabetes; none of whom had statin intolerance. After withdrawal of statins for two months, we obtained blood samples, performed vastus lateralis muscle biopsies, and assessed whole body resting energy expenditure (REE). We then re-initiated therapy using simvastatin, 20 mg/day, for one month before repeating these studies. As expected, simvastatin lowered LDL, but did not induce myalgias or significant elevations in serum creatine kinase. However, we found subtle but significant reductions in muscle citrate synthase activity and REE. In addition, quantitative PCR and gene set enrichment analysis of muscle samples revealed significantly repressed gene sets involved in mitochondrial function and induced gene sets involved in remodeling of the extracellular matrix. Further, the effects of simvastatin on muscle gene sets showed some similarities to previously described changes that occur in Duchenne muscular dystrophy, polymyositis, and dermatomyositis. Although statins inhibit an early step in coenzyme Q (CoQ) biosynthesis, we observed no differences in CoQ content within skeletal muscle mitochondria, muscle tissue, or circulating platelets. In summary, we report subtle changes in whole body energetics, mitochondrial citrate synthase activity, and microarray data consistent with subclinical myopathy. Although the benefits of statin therapy are clear, further understanding of muscular perturbations should help guide safety and tolerability.

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“…Statin-mediated impairment of the synthesis of ATP and ketone bodies has been demonstrated in humans [86], and as ATP is used as energy currency, chronic statin use may cause cellular energy depletion and ischemia. Rhabdomyolysis and/or muscle pains are highly likely a consequence of statin mitochondrial toxicity.…”

Section: Critical Review Of the Consensus Statement 2017 Based On Stamentioning

confidence: 99%

“…Astronauts develop osteoporosis during stays in space possibly due to decreased physical activity and tensile load exerted on bone tissue, and age-related osteoporosis is likely to share the same mechanism. In statin users, skeletal muscle lesions leading to rhabdomyolysis and/or muscle pains reduce the ability to perform the physical activity necessary to protect against bone fracture [86, 106]. …”

Section: Critical Review Of the Consensus Statement 2017 Based On Stamentioning

confidence: 99%

A Critical Review of the Consensus Statement from the European Atherosclerosis Society Consensus Panel 2017

Okuyama

Hamazaki²,

Hama³

et al. 2018

Pharmacology

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Background: The Consensus Statement from the European Atherosclerosis Society (EAS) Consensus Panel 2017 concludes on the basis of 3 different types of clinical studies that low-density lipoprotein (LDL) causes atherosclerotic cardiovascular disease (ASCVD). In Mendelian randomization studies, rare genetic mutations affecting LDL receptor function were found to cause higher or lower LDL-C levels, which are associated with correspondingly altered ASCVD risk. In prospective cohort studies and randomized controlled trials (RCTs) of statins, a remarkably consistent log-linear association was demonstrated between the absolute magnitude of LDL-C exposure and ASCVD risk. The EAS Statement proposes that any mechanism of lowering plasma LDL concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C. However, as we explain, we do not find this conclusion acceptable. Summary: Our review points out that different interpretations are possible for the results of Mendelian randomization studies. As for prospective cohort studies, many inconsistent reports on the association of LDL-C and ASCVD were disregarded when drafting the Statement, reports with and without genetic factors related to LDL receptor function should be analyzed separately, and the term ASCVD in the Statement is used inappropriately because myocardial infarction and cerebral infarction differ in their association with LDL-C. As for RCTs, clinical reports on statins published before and after the implementation of new regulations affecting clinical trials (2004/2005) should not both be included in meta-analyses because the evaluated efficacy of statins changed markedly, and the irreversible adverse effects of statins need to be evaluated more rigorously now that their mechanisms have been elucidated. Key Messages: Apart from the EAS hypothesis that LDL causes ASCVD, recent pharmacological/biochemical studies, as summarized in this review and elsewhere, have revealed that atherosclerosis is caused by statins taken to lower LDL-C, as well as by warfarin and some types of vegetable fats and oils, in the absence of significantly elevated LDL-C levels. Thus, the promotion of statin treatment by the Statement is rather risky and we do not feel that the conclusions are justified for the prevention of ASCVD.

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Simvastatin Effects on Skeletal Muscle

Cited by 151 publications

References 44 publications

Effects of exercise training on mitochondrial function in patients with type 2 diabetes

Effects of exercise training on mitochondrial function in patients with type 2 diabetes

Evidence for metabolic aberrations in asymptomatic persons with type 2 diabetes after initiation of simvastatin therapy

A Critical Review of the Consensus Statement from the European Atherosclerosis Society Consensus Panel 2017

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