Pleiotropic effects of metformin to rescue statin-induced muscle injury and insulin resistance: A proposed mechanism and potential clinical implications

Carris, Nicholas W.; Tipparaju, Srinivas M.; Magness, David J.; Chapalamadugu, Kalyan C.; Magness, Ronald R.

doi:10.1016/j.mehy.2017.07.007

Cited by 11 publications

(18 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To our knowledge, this is the first report associating metformin with a reduced incidence of muscle pain in statin-treated patients. In line with the hypothesis we first proposed, 8 metformin indeed demonstrated a greater odds reduction in early-reported muscle pain, prior to when more patients in the statin-only group may have initiated metformin or discontinued statin therapy. Additionally, there was a demonstrated similar benefit for metformin in 2 measures of mild-tomoderate statin-induced muscle pain.…”

Section: Discussionsupporting

confidence: 85%

“…To our knowledge, this is the first study to identify a drug as a potential treatment option for statin-induced muscle pain and provides preliminary support for our proposal that metformin's mechanism of action alleviates/prevents statin-induced muscle pain. 8 Because of metformin's co-indications, these results have the potential for application in clinical practice in non-severe cases of statininduced muscle pain that do not require statin discontinuation or switching. Validation of these results is required before wider use can be considered.…”

Section: Discussionmentioning

confidence: 99%

“…The purported hypothesized mechanism exploits metformin's effect on mitochondrial oxidative stress and its effect on AMP‐activated protein kinase (AMPK). It is known that AMPK counter‐regulates downstream mediators of the insulin‐like growth factor 1/phosphatidylinositol‐3‐kinase/Protein Kinase B (IGF‐1/PI3K/AKT) pathway, which is associated with statin‐induced muscle pain . Therefore, the goal of the present study was to assess metformin's effects on mild‐to‐moderate muscle pain in statin‐treated patients.…”

Section: Introductionmentioning

confidence: 99%

“…2 Multiple agents for the alleviation/prevention of statin-induced muscle pain have been studied; however, results have been inconclusive. 6,7 We proposed that metformin can alleviate/prevent statin-induced muscle pain, 8 which may improve statin adherence and thus statinrelated cardiovascular outcomes. The purported hypothesized mechanism exploits metformin's effect on mitochondrial oxidative stress and its effect on AMP-activated protein kinase (AMPK).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Metformin's impact on statin‐associated muscle symptoms: An analysis of ACCORD study data and research materials from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center

Carris

Tsalatsanis

Tipparaju

et al. 2018

Diabetes Obesity Metabolism

Self Cite

View full text Add to dashboard Cite

Statins are widely prescribed, yet statin muscle pain limits their use, leading to increased cardiovascular risk. No validated therapy for statin muscle pain exists. The goal of the study was to assess whether metformin was associated with reduced muscle pain. A secondary analysis of data from the ACCORD trial was performed. An ACCORD sub-study assessed patients for muscle cramps and leg/calve pain while walking, typical non-severe statin muscle pain symptoms. We compared muscle pain between patients using a statin (n = 445) or both a statin and metformin (n = 869) at baseline. Overall patient characteristics were balanced between groups. Unadjusted analysis showed fewer reports of muscle cramps (35%) and leg/calve pain while walking (40%) with statins and metformin compared to statin only (muscle cramps, 42%; leg/calve pain while walking, 47%). Multivariable regression demonstrated a 22% odds reduction for muscle cramps (P = 0.049) and a 29% odds reduction for leg/calve pain while walking (P = 0.01). Metformin appears to reduce the risk of non-severe statin muscle pain and additional research is needed to confirm the findings and assess metformin's impact on statin adherence and related cardiovascular outcomes.

show abstract

Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Metformin's impact on statin‐associated muscle symptoms: An analysis of ACCORD study data and research materials from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center

Carris

Tsalatsanis

Tipparaju

et al. 2018

Diabetes Obesity Metabolism

Self Cite

View full text Add to dashboard Cite

show abstract

“…Numerous side effects are associated with statin use, including myopathic effects, short-term memory loss, abnormal liver function, glucose intolerance, hyperglycemia, and increased risk for diabetes (Golomb and Evans, 2008;Davies et al, 2016;Ramkumar et al, 2016). Up to 25% of statin users report muscle symptoms, cramping, soreness, and fatigue, thereby forcing many patients to switch to lower doses, switch to lower potency statins, or to withdraw (Carris et al, 2017). Statins are also associated with ocular adverse effects, including blurred vision, visual impairment, visual-field defect, reduced visual acuity, myopia, hypermetropia, presbyopia, and astigmatism (Machan et al, 2012;Mizranita and Pratisto, 2015).…”

Section: Introductionmentioning

confidence: 99%

Statins Perturb GβγSignaling and Cell Behavior in a GγSubtype Dependent Manner

et al. 2019

View full text Add to dashboard Cite

Guanine nucleotide-binding proteins (G proteins) facilitate the transduction of external signals to the cell interior, regulate most eukaryotic signaling, and thus have become crucial disease drivers. G proteins largely function at the inner leaflet of the plasma membrane (PM) using covalently attached lipid anchors. Both small monomeric and heterotrimeric G proteins are primarily prenylated, either with a 15-carbon farnesyl or a 20-carbon geranylgeranyl polyunsaturated lipid. The mevalonate [3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase] pathway synthesizes lipids for G-protein prenylation. It is also the source of the precursor lipids for many biomolecules, including cholesterol. Consequently, the rate-limiting enzymes of the mevalonate pathway are major targets for cholesterol-lowering medications and anticancer drug development. Although prenylated G protein g (Gg) is essential for G protein-coupled receptor (GPCR)-mediated signaling, how mevalonate pathway inhibitors, statins, influence subcellular distribution of Gbg dimer and Gabg heterotrimer, as well as their signaling upon GPCR activation, is poorly understood. The present study shows that clinically used statins not only significantly disrupt PM localization of Gbg but also perturb GPCR-G protein signaling and associated cell behaviors. The results also demonstrate that the efficiency of prenylation inhibition by statins is Gg subtype-dependent and is more effective toward farnesylated Gg types. Since Gg is required for Gbg signaling and shows a cell-and tissue-specific subtype distribution, the present study can help understand the mechanisms underlying clinical outcomes of statin use in patients. This work also reveals the potential of statins as clinically usable drugs to control selected GPCR-G protein signaling.

show abstract

Impact of metformin on statin‐associated myopathy risks in dyslipidemia patients

Bak

Moon

et al. 2023

Pharmacology Res & Perspec

View full text Add to dashboard Cite

A growing number of patients with metabolic disorders are receiving statin and antidiabetic therapies as comedications. A signal of increased risk of myotoxicity due to potential interactions between antidiabetics and statins has been detected in previous studies. To investigate the effects of metformin on myopathy risks when added to preexisting statin therapy in dyslipidemia patients, we performed a retrospective cohort study using the Korean national health insurance data in statin‐treated dyslipidemia patients with or without concomitant metformin use. We compared the risk of myopathy in statin + metformin users against statin‐only users. Hazard ratios (HRs) and 95% confidence intervals (CIs) have been calculated following propensity score (PS) matching between study groups and subsequent stratification per patient factors. We included 4092 and 8161 patients in PS‐matched statin + metformin and statin‐only groups, respectively. The risk of myopathy decreased when metformin was used together with statins (adjusted HR 0.84; 95% CI 0.71–0.99). In subgroup analyses per individual statin agent and in stratified risk analyses, no specific statin agents or patient factors were associated with statistically significant myopathy risk. This study found that a comedication with metformin was associated with decreased myopathy risk in statin‐treated dyslipidemia patients compared to statin‐only users. Our findings suggest that metformin may provide protective effects on potential muscle toxicities induced by statin therapy.

show abstract

Pleiotropic effects of metformin to rescue statin-induced muscle injury and insulin resistance: A proposed mechanism and potential clinical implications

Cited by 11 publications

References 58 publications

Metformin's impact on statin‐associated muscle symptoms: An analysis of ACCORD study data and research materials from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center

Metformin's impact on statin‐associated muscle symptoms: An analysis of ACCORD study data and research materials from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center

Statins Perturb GβγSignaling and Cell Behavior in a GγSubtype Dependent Manner

Impact of metformin on statin‐associated myopathy risks in dyslipidemia patients

Contact Info

Product

Resources

About