Myotoxic reactions to lipid-lowering therapy are associated with altered oxidation of fatty acids

Phillips, Paul S; Ciaraldi, Theodore P.; Kim, Dong-Lim; Verity, M. Anthony; Wolfson, Tanya; Henry, Robert R.

doi:10.1007/s12020-008-9126-2

Cited by 13 publications

(7 citation statements)

References 37 publications

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“…Although depletion of coenzyme Q10 is thought to affect oxidative phosphorylation and protection from statin-induced oxidative stress, compelling clinical evidence is lacking regarding the efficacy of coenzyme Q10 treatment of statin myopathy. 18 There is recent evidence to indicate that fatty acid oxidation is perturbed in cultured myotubes of statin intolerant (myalgic) patients, 19 a finding that differs from patients with rhabdomyolysis. 20 Such data suggest that the mechanisms of statin toxicity are different between those affected with myalgia and rhabdomyolysis.…”

mentioning

confidence: 99%

Human Skeletal Muscle Drug Transporters Determine Local Exposure and Toxicity of Statins

Knauer

Urquhart

Schwabedissen

et al. 2010

Circulation Research

182

146

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Rationale: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, are important drugs used in the treatment and prevention of cardiovascular disease. Although statins are well tolerated, many patients develop myopathy manifesting as muscle aches and pain. Rhabdomyolysis is a rare but severe toxicity of statins. MG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors, statins, are highly effective drugs for the treatment of hypercholesterolemia, a major risk factor of cardiovascular disease. Statins inhibit the synthesis of mevalonate, the rate-limiting step in cholesterol biosynthesis. 1,2 Although statins are generally well tolerated, 3 skeletal muscle side effects are commonly reported among those treated. One such side effect, myalgia, which is defined as muscle aches or weakness in the absence of blood creatine kinase elevation, occurs in 5% to 15% of statin-treated patients. 2,4 -8 In rare cases, potentially life-threatening statin-induced rhabdomyolysis may occur, a condition characterized by acute muscle damage, resulting in pronounced elevation in creatine kinase levels and possible renal failure. 9 The pathophysiology of statin-induced myopathy is not completely understood. The leading mechanism suggests a role for cellular depletion of secondary metabolic intermediates of mevalonate in the development of statin-induced myotoxicity. 10 In addition to decreased cholesterol synthesis, HMG-CoA reductase inhibition by statins causes a commensurate reduction in the levels of downstream metabolic products including isoprenoids, dolichol, and ubiquinone (coenzyme Q10). 10 -13 Among these are the isoprenoid secondary metabolic intermediates geranylgeranylpyrophosphate and farnesylpyrophosphate that are involved in protein isoprenylation and activation of small GTPases such as Rho and Rab. The important role for diminished isoprenylation in the mechanism of statin myotoxicity is related to induction of the muscle atrophy-linked protein atrogin-1. 12 This is highlighted by the findings that supplementation of geranylgeranylpyrophosphate to cultured skeletal myotubes or isolated myofibers treated with statins leads to attenuation of toxicity, 11,13-15 whereas inactivation of a Rab and RhoA induces toxicity. 11,13 Decreased geranylgeranylation of small GT-

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mentioning

confidence: 99%

Human Skeletal Muscle Drug Transporters Determine Local Exposure and Toxicity of Statins

Knauer

Urquhart

Schwabedissen

et al. 2010

Circulation Research

182

146

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“…The mechanism by which statins cause myopathy is unclear, but may involve reduction in membrane cholesterol content, fatty acid oxidation and mitochondrial function in skeletal muscle, and a genetic aetiology …”

Section: Need For New Therapies Targeting Apob100‐containing Lipoprotmentioning

confidence: 99%

“…26,54 The mechanism by which statins cause myopathy is unclear, but may involve reduction in membrane cholesterol content, fatty acid oxidation and mitochondrial function in skeletal muscle, and a genetic aetiology. 26,56,57 The inability of a multitude of clinical trials to identify SAMS as a problem with statin therapy strengthens the need for rigorous postmarketing surveillance in the non-clinical trial setting.…”

Section: Statin Intolerancementioning

confidence: 99%

PCSK9 in context: A contemporary review of an important biological target for the prevention and treatment of atherosclerotic cardiovascular disease

Page

Watts

2017

Diabetes Obesity Metabolism

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The identification of the critical role of proprotein convertase subtilisin/kexin type 9 (PCSK9) has rapidly led to the development of PCSK9 inhibition with monoclonal antibodies (mAbs). PCSK9 mAbs are already in limited clinical use and are the subject of major cardiovascular outcomes trials, which, if universally positive, could see much wider clinical application of these agents. Patients with familial hypercholesterolaemia are the most obvious candidates for these drugs, but other patients with elevated cardiovascular risk, statin intolerance or hyperlipoproteinaemia(a) may also benefit. PCSK9 mAbs, administered once or twice monthly, reduce LDL cholesterol levels by 50% to 70%, and appear to be safe and acceptable to patients over at least 2 years of treatment; however, treatment-emergent adverse effects are not always identified in clinical trials, as well-evidenced by statin myopathy. Inclisiran is a promising RNA-based therapy that promotes the degradation of PCSK9 mRNA transcripts and has similar efficacy to mAbs, but with a much longer duration of action. The cost-effectiveness and long-term safety of therapies targeted at inhibiting PCSK9 remain to be demonstrated if they are to be used widely in coronary prevention.

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“…The most popular involves reduction in ubiquinone, as it plays a role in muscle cell energy production. [41][42][43] Other factors continue to be implicated: elevated levels of β-sitosterol due to reduced fat synthesis and increased β-oxidation 44 and altered expression of atrogin-1, a muscle-specific ubiquitin protein ligase that plays a role in toxicity. 45 In approaching patients with statin-induced muscle problems, a commonly used strategy is statin withdrawal and rechallenge, in which the statin is stopped for at least 2 weeks and then restarted to see if symptoms return.…”

Section: Benefits Of Statinsmentioning

confidence: 99%

Statin-Associated Adverse Events

Yuet

Khine

Ahmad

2015

Clinical Medicine Insights: Therapeutics

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Although statins are well tolerated, their widespread use has raised awareness of rare adverse events. For example, the United States Food and Drug Administration (FDA) has issued product label warnings about statin-associated myopathy, incident diabetes, and cognitive impairment. Additional statin-associated adverse effects include proteinuria, transaminitis, and hemorrhagic stroke. The underlying pathophysiology of these adverse events remains unclear, and thus little guidance exists on addressing these issues at the bedside. Although statin-associated myopathy is common, many patients eventually tolerate a statin-albeit at less than ideal doses. Incident diabetes remains difficult to predict, but high statin potency, increasing age, and preexisting diabetes risk factors may predispose patients. Cognitive impairment-described mostly in case reports-may resolve after discontinuation of the offending statin. Rosuvastatin is linked to dose-dependent proteinuria. Elevated transaminases are reversible and unlikely to cause severe consequences. History of cerebrovascular disease increases the risk of hemorrhagic stroke on statin therapy. Overall, a thorough understanding of statin-associated adverse events will help health care providers manage patients who develop these complications. Here, we review the evidence for several statin-associated adverse effects and the implications for clinical practice.

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Myotoxic reactions to lipid-lowering therapy are associated with altered oxidation of fatty acids

Cited by 13 publications

References 37 publications

Human Skeletal Muscle Drug Transporters Determine Local Exposure and Toxicity of Statins

Human Skeletal Muscle Drug Transporters Determine Local Exposure and Toxicity of Statins

PCSK9 in context: A contemporary review of an important biological target for the prevention and treatment of atherosclerotic cardiovascular disease

Statin-Associated Adverse Events

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