Rationale for investigating metformin as a protectant against statin-associated muscle symptoms

Elsaid, Ossama; Taylor, Beth A.; Zaleski, Amanda L.; Panza, Gregory A.; Thompson, Paul D.

doi:10.1016/j.jacl.2017.06.019

Cited by 9 publications

(14 citation statements)

References 91 publications

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“…Because of its ability to regulate metabolism, metformin is actively studied for protective therapies in aging, neurodegenerative disease, and cancer. Studies have shown that metformin protects cells in vivo from brain ischemia/reperfusion injury, cardiovascular disease, and statin-associated muscle symptoms (18)(19)(20).…”

mentioning

confidence: 99%

Stimulation of AMPK prevents degeneration of photoreceptors and the retinal pigment epithelium

Kong

Wang

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

126

115

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Retinal degenerative diseases are generally characterized by a permanent loss of light-sensitive retinal neurons known as photoreceptors, or their support cells, the retinal pigmented epithelium (RPE). Metabolic dysfunction has been implicated as a common mechanism of degeneration. In this study, we used the drug metformin in a gain-of-function approach to activate adenosine monophosphate-activated protein kinase (AMPK). We found that treatment protected photoreceptors and the RPE from acute injury and delayed inherited retinal degeneration. Protection was associated with decreased oxidative stress, decreased DNA damage, and increased mitochondrial energy production. To determine whether protection was a local or a systemic effect of metformin, we used AMPK retinal knockout mice and found that local expression of AMPK catalytic subunit α2 was required for metformin-induced protection. Our data demonstrate that increasing the activity of AMPK in retinal neurons or glia can delay or prevent degeneration of photoreceptors and the RPE from multiple types of cell-death triggers.

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mentioning

confidence: 99%

Stimulation of AMPK prevents degeneration of photoreceptors and the retinal pigment epithelium

Kong

Wang

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

126

115

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“…Statin use is not well-tolerated in some individuals and can be associated with myotoxicity-induced muscle pain. Reduced mitochondrial content and function, disruptions in glucose and calcium metabolism, and inhibition of mTORC1 signaling resulting in protein breakdown via FOXO and atrogin-1 pathways are proposed mechanisms for statin intolerance ( Bonifacio et al, 2015 ; Du Souich et al, 2017 ; Elsaid et al, 2017 ). A new report also shows metformin affects the FOXO-myostatin signaling axis causing muscle atrophy ( Kang et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Potential Benefits of Combined Statin and Metformin Therapy on Resistance Training Response in Older Individuals

et al. 2022

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Metformin and statins are currently the focus of large clinical trials testing their ability to counter age-associated declines in health, but recent reports suggest that both may negatively affect skeletal muscle response to exercise. However, it has also been suggested that metformin may act as a possible protectant of statin-related muscle symptoms. The potential impact of combined drug use on the hypertrophic response to resistance exercise in healthy older adults has not been described. We present secondary statin analyses of data from the MASTERS trial where metformin blunted the hypertrophy response in healthy participants (>65 years) following 14 weeks of progressive resistance training (PRT) when compared to identical placebo treatment (n = 94). Approximately one-third of MASTERS participants were taking prescribed statins. Combined metformin and statin resulted in rescue of the metformin-mediated impaired growth response to PRT but did not significantly affect strength. Improved muscle fiber growth may be associated with medication-induced increased abundance of CD11b+/CD206+ M2-like macrophages. Sarcopenia is a significant problem with aging and this study identifies a potential interaction between these commonly used drugs which may help prevent metformin-related blunting of the beneficial effects of PRT.Trial Registration: ClinicalTrials.gov, NCT02308228, Registered on 25 November 2014.

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“…This forces the liver to use cholesterol to increase bile acid production 138 . On the contrary, by acting as a statin, metformin could potentially worsen muscle symptoms 139 . AMPK activation is central to the hypothetical mechanisms by which metformin might produce SAMS.…”

Section: Metformin and Statinsmentioning

confidence: 99%

“…138 On the contrary, by acting as a statin, metformin could potentially worsen muscle symptoms. 139 AMPK activation is central to the hypothetical mechanisms by which metformin might produce SAMS. As mentioned above, AMPK phosphorylation stimulates pathways that generate ATP and inhibits pathways that consume ATP.…”

Section: Me Tformin and S Tatin Smentioning

confidence: 99%

Rationale for the use of metformin and exercise to counteract statin‐associated side effects

Haxhi

Thompson

2020

Int. J. Clin. Pract.

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Statins are the most widely prescribed drugs for lowering low-density lipoprotein cholesterol (LDL-C) and reducing cardiovascular morbidity and mortality. 1 The benefits of statin therapy are supported by highquality research studies indicating that every 1 mmol/L (38.7 mg/dL) reduction in LDL-C is associated with a 22% relative risk reduction in cardiovascular disease (CVD) events. 2 It is now possible, with the development of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, to produce very large reductions in LDL-C. 3,4 Median LDL-C levels as low as 30 mg/dL in the FOURIER Study were associated with reductions in CVD events, with no evidence of safety issues over the 2.2 years of the study duration. 5 Statins are well-tolerated, but have two main safety concerns: statin-associated muscle symptoms (SAMS) and new-onset type 2 diabetes (NOD). 6 This review focuses on these two statin side effects. We will discuss the responsible mechanisms of statin-associated SAMS and NOD.Then, we will provide a rationale for the potential role of Metformin and exercise in the treatment/prevention of SAMS and NOD (Figure 1). | ME THODSA PubMed (https://pubmed.ncbi.nlm.nih.gov/) search was carried out to identify the relevant literature. The following key words were used: statins, statin-associated muscle symptoms, statin myalgia, statin-associated diabetes, metformin and statins, exercise and statins. We included human, as well as animal and in vitro mechanistic studies. Articles published in the last 20 years in English language were included. Additional relevant articles were identified from the reference lists of selected articles and from a hand search of pertinent journals. | SAMS AND D IAB E TE SSAMS are defined as "muscle pain, weakness and aches, usually symmetrical and proximal, affecting the thighs, buttocks, calves and back muscles, not normally associated with marked creatine kinase (CK) elevation". 7 SAMS are statins' most prevalent adverse event,

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Rationale for investigating metformin as a protectant against statin-associated muscle symptoms

Cited by 9 publications

References 91 publications

Stimulation of AMPK prevents degeneration of photoreceptors and the retinal pigment epithelium

Stimulation of AMPK prevents degeneration of photoreceptors and the retinal pigment epithelium

Potential Benefits of Combined Statin and Metformin Therapy on Resistance Training Response in Older Individuals

Rationale for the use of metformin and exercise to counteract statin‐associated side effects

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