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Myotoxicity of statins: Mechanism of action
Patrick du Souich1, Ghislaine Roederer2, Robert Dufour3
1Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada; Clinique de Nutrition, Métabolisme et Athérosclérose, Institut de Recherche Clinique de Montréal, 120, Avenue des Pins Ouest, Montréal, Québec, Canada.
Abstract:
Statins are effective drugs to reduce cardiovascular events secondary to dyslipidemia; however, they cause frequent undesirable side effects. The incidence of statin-induced myotoxicity (SIM) is presented by 7 to 29% of patients, depending upon the report. SIM may develop in presence of abnormally high concentrations of statins in the myocyte and/or in presence of muscular conditions that may predispose to SIM. High concentrations of statins in the myocyte may occur whenever the activity of liver influx membrane transporters, namely OATP1B1, of drug metabolizing enzymes, and of liver and muscular efflux transporters, MDR1 and BCRP, is reduced. In the muscle, conditions that may predispose to SIM include mitochondrial damage with disruption of the mitochondrial respiratory chain and decreased production of ATP, increase of ROS, and leak of cytochrome c and Ca2+. In the sarcoplasma, statins activate MAPK and diminish the RhoA/AKT/mTOR/PGC-1α pathway. All these effects contribute to activate apoptosis, proteolysis, and muscle remodeling. Moreover, in the sarcoplasma, statins can reduce the resting chloride channel conductance, as well as lactate efflux. These changes will be responsible of fatigue, cramps, myalgia and elevation of serum CK. To date, besides avoiding drug-drug interactions and alcohol consumption, and correcting hypothyroidism, two strategies could be useful to prevent/diminish SIM, e.g. gradual dose titration with statins less prone to produce SIM, and high supplements of vitamin D in subjects with low plasma concentrations of 25(OH) D3.
Insights
Statin-induced myotoxicity (SIM) affects 7-29% of patients due to high statin levels or muscle conditions. Gradual dose titration and vitamin D supplementation may help prevent or reduce SIM.
Area of Science:
- Pharmacology
- Biochemistry
- Cardiovascular Medicine
Background:
- Statins effectively reduce cardiovascular events in dyslipidemia but can cause myotoxicity (SIM).
- SIM incidence ranges from 7% to 29%, linked to high intracellular statin concentrations or predisposing muscle conditions.
- Mechanisms involve impaired drug transporters (OATP1B1, MDR1, BCRP), mitochondrial dysfunction, oxidative stress, and altered cellular signaling pathways.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying statin-induced myotoxicity (SIM).
- To identify factors contributing to SIM development and potential strategies for prevention or mitigation.
Main Methods:
- Review of existing literature on statin pharmacology, cellular transport, and muscle physiology.
- Analysis of molecular pathways affected by statins in myocytes, including mitochondrial function, oxidative stress, and signaling cascades (MAPK, RhoA/AKT/mTOR/PGC-1α).
Main Results:
- High intracellular statin concentrations, due to reduced transporter activity (OATP1B1, MDR1, BCRP), contribute to SIM.
- Muscle conditions like mitochondrial damage, decreased ATP production, increased ROS, and calcium/cytochrome c leak predispose to SIM.
- Statins activate MAPK, inhibit the RhoA/AKT/mTOR/PGC-1α pathway, leading to apoptosis, proteolysis, and muscle remodeling, causing symptoms like fatigue, cramps, and elevated CK.
Conclusions:
- Preventive strategies include gradual statin dose titration with less myotoxic formulations and vitamin D supplementation for individuals with low 25(OH)D3 levels.
- Avoiding drug-drug interactions, alcohol, and correcting hypothyroidism are also crucial for managing SIM risk.
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