Metformin Does Not Affect Clinically Relevant Outcomes in Patients with Idiopathic Pulmonary Fibrosis

Spagnolo, Paolo; Kreuter, Michael; Maher, Toby M.; Wuyts, Wim; Bonella, Francesco; Corte, Tamera J.; Kopf, Stefan; Weycker, Derek; Kirchgaessler, Klaus-Uwe; Ryerson, Christopher J.

doi:10.1159/000489668

Cited by 48 publications

(37 citation statements)

References 35 publications

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“…Metformin reduces elastase-induced emphysema in mice (54) and is well tolerated in COPD patients, although measurements of senescence have not been made (84). Metformin is effective in reversing bleomycin-induced fibrosis (48), but in patients being treated with metformin for diabetes there was no obvious effect on disease progression in IPF (85).…”

Section: Targeting Senescence Pathwaysmentioning

confidence: 99%

Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases

Barnes

Baker

Donnelly

2019

Am J Respir Crit Care Med

343

264

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Cellular senescence is now considered an important driving mechanism for chronic lung diseases, particularly COPD and idiopathic pulmonary fibrosis. Cellular senescence is due to replicative and stress-related senescence with activation of p53 and p16 INK4a respectively, leading to activation of p21 CIP1 and cell cycle arrest. Senescent cells secrete multiple inflammatory proteins known as the senescence-associated secretory phenotype (SASP), leading to low grade chronic inflammation, which further drives senescence. Loss of key anti-aging molecules sirtuin-1 and sirtuin-6 may be important in acceleration of aging and arises from oxidative stress reducing phosphatase PTEN, thereby activating PI3K (phosphoinositide-3-kinase) and mTOR (mammalian target of rapamycin). MicroRNA-34a, which is regulated by PI3K-mTOR signaling, plays a pivotal role in reducing sirtuin-1/6 and its inhibition with an antagomir results in their restoration, reducing markers of senescence, reducing SASP and reversing cell cycle arrest in epithelial cells from peripheral airways of COPD patients. MiR-570 is also involved in reduction of sirtuin-1 and cellular senescence and is activated by p38 MAP kinase. These miRNAs may be released from cells in extracellular vesicles that are taken up by other cells, thereby spreading senescence locally within the lung but outside the lung through the circulation; this may account for comorbidities of COPD and other lung diseases. Understanding the mechanisms of cellular senescence may result in new treatments for chronic lung disease, either by inhibiting PI3K-mTOR signaling, by inhibiting specific miRNAs or by deletion of senescent cells with senolytic therapies, already shown to be effective in experimental lung fibrosis.

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Section: Targeting Senescence Pathwaysmentioning

confidence: 99%

Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases

Barnes

Baker

Donnelly

2019

Am J Respir Crit Care Med

343

264

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Section: Discussionmentioning

confidence: 99%

“…In a recent report, post-hoc analysis was performed on IPF patients derived from the placebo arms of three phase 3, double-blind, controlled trials of pirfenidone 50 . In that study, 71 metformin users did not present improvements in clinical outcomes compared to 553 non-metformin users 51 . As pointed out by Tzouvelekis and colleagues, these data cannot be generalized into the global IPF population due to many caveats in the study design including the post-hoc nature of the study, the low number of metformin users, lack of stringent criteria for diagnosis and assessment of diabetes control, inability to link metformin mechanisms to IPF pathogenesis or to delineate drug-drug interactions 52 .…”

Section: Discussionmentioning

confidence: 99%

Metformin induces lipogenic differentiation in myofibroblasts to reverse mouse and human lung fibrosis

Kheirollahi

Wasnick

Biasin

et al. 2018

Preprint

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Idiopathic pulmonary fibrosis is a fatal, incurable lung disease in which the intricate alveolar network of the human lung is progressively replaced by fibrotic scars, eventually leading to respiratory failure. Myofibroblasts are the effector cells that lead to abnormal deposition of extracellular matrix proteins and therefore mediate fibrotic disease not only in the lung but also in other organs. Emerging literature suggests a correlation between fibrosis and metabolic alterations in IPF. In this study, we show that the first-line antidiabetic drug, metformin, exerts potent antifibrotic effects in the lung by modulating metabolic pathways, inhibiting TGFβ1 action, suppressing collagen formation, activating PPARγ signaling and inducing lipogenic differentiation in lung myofibroblasts derived from human patients. Using genetic lineage tracing in a murine model of lung fibrosis, we show that metformin alters the fate of myofibroblasts and accelerates fibrosis resolution by inducing myofibroblast-tolipofibroblast transdifferentiation. Detailed pathway analysis showed that the reduction of collagen synthesis was largely AMPK-dependent, whereas the transdifferentiation of myo-to lipofibroblasts occurred in a BMP2-PPARγ-dependent fashion and was largely AMPK-independent. Our data report an unprecedented role for metformin in lung fibrosis, thus warranting further therapeutic evaluation.

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“…In this issue of Respiration, Spagnolo et al [4] perform a post-hoc analysis on the efficacy of metformin in 624 patients with IPF with or without diabetes or insulin glucose tolerance derived from the placebo arms of the 3 randomized controlled trials of pirfenidone. The study rationale was based on: (1) epidemiological data linking diabetes with IPF development and progression (knowledge of disease phenotypes and comorbidities) [5] and (2) pre-clinical evidence showing that metformin may exert anti-fibrotic properties through regulation of cellular bioenergetics and autophagy via activation of AMP-activated protein kinase in experimental models of lung fibrosis (knowledge of drug and disease mechanisms) [6][7][8].…”

mentioning

confidence: 99%