Combination Metformin and Low-Dose Nintedanib Reduces Pulmonary Fibrosis

This article is part of Pulmonology Advisor‘s coverage of the CHEST 2019 meeting, taking place in New Orleans, LA. Our staff will report on medical research related to asthma, COPD, critical care medicine, and more conducted by experts in the field. Check back regularly for more news from CHEST 2019.

NEW ORLEANS — Metformin was effective in reducing pulmonary fibrosis in human idiopathic pulmonary fibrosis (IPF) fibroblasts and when used in combination with low-dose nintedanib, demonstrated a synergistic, antifibrotic effect. This research was presented at the CHEST Annual Meeting 2019, held October 19 to 23, in New Orleans, Louisiana.

Investigators of this study sought to examine whether metformin and low-dose nintedanib combination therapy can reduce pulmonary fibrosis in vitro. The researchers inoculated human IPF fibroblasts with low doses of metformin (250 μM, 125 μM, 62.5 μM, and 32.5 μM) followed by 24 hours of transforming growth factor-beta (TGF-β) stimulation. To quantify the fibronectin protein production in TGF-β stimulated fibroblasts, the investigators performed enzyme-linked immunosorbent assays (ELISAs). Analysis of the pooled ELISAs shows that 250 μM and 125 μM were the most effective doses of metformin, lowering fibronectin levels to an average 69.3% (±12.5; P =.03) and 64.2% (±12.1; P =.006), respectively.

When human IPF fibroblasts were treated with both metformin and nintedanib followed by TGF-β stimulation for 24 hours, the combination had a significant antifibrotic effect. Combination therapy using 250 μM metformin reduced fibronectin levels to 25.6% and 125 μM metformin reduced fibronectin levels to 13.0%. Although nintedanib was intended to alleviate the side-effect profile of metformin, 0.25 μM of nintedanib alone lowered fibronectin levels to 39.3% of the total TGF-β stimulated fibroblasts. These findings were consistent when metformin was combined with higher doses of nintedanib (1.0 μM and 0.5 μM).

The investigators concluded that these results validate the antifibrotic effect of metformin on human IPF fibroblasts and that they demonstrate the synergistic effect of combined metformin and low-dose nintedanib for lowering fibronectin levels in pulmonary fibrosis. Therapy with metformin and nintedanib should be further studied to guide the future of IPF treatment.

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Reference

Vu A, Kottom T, Schaefbauer K, Limper A. Metformin and low dose nintedanib as a novel combination therapy to reduce pulmonary fibrosis in human TGF-beta stimulated fibroblasts. Presented at: CHEST Annual Meeting 2019; October 19-23, 2019; New Orleans, LA. Abstract 4.