Metformin: Experimental and Clinical Evidence for a Potential Role in Emphysema Treatment

Rationale: Cigarette smoke (CS) inhalation triggers oxidative stress and inflammation, leading to accelerated lung aging, apoptosis, and emphysema, as well as systemic pathologies. Metformin is beneficial for protecting against aging-related diseases. Objectives: We sought to investigate whether metformin may ameliorate CS-induced pathologies of emphysematous chronic obstructive pulmonary disease (COPD). Methods: Mice were exposed chronically to CS and fedmetforminenriched chow for the second half of exposure. Lung, kidney, andmuscle pathologies, lung proteostasis, endoplasmic reticulum(ER) stress, mitochondrial function, andmediators ofmetformin effects in vivo and/ or in vitro were studied. We evaluated the association ofmetformin use with indices of emphysema progression over 5 years of follow-up among the COPDGene (Genetic Epidemiology of COPD) study participants. The association ofmetformin usewith the percentage of emphysema and adjusted lung density was estimated by using a linearmixedmodel. Measurements and Main Results: Metformin protected against CS-induced pulmonary inflammation and airspace enlargement; small airway remodeling, glomerular shrinkage, oxidative stress, apoptosis, telomere damage, aging, dysmetabolism in vivo and in vitro; and ER stress. The AMPK (AMP-activated protein kinase) pathway was central to metformin's protective action. Within COPDGene, participants receiving metformin compared with those not receiving it had a slower progression of emphysema (-0.92%; 95% confidence interval [CI], 21.7% to -0.14%; P= 0.02) and a slower adjusted lung density decrease (2.2 g/L; 95% CI, 0.43 to 4.0 g/L; P= 0.01). Conclusions: Metformin protected against CS-induced lung, renal, and muscle injury; mitochondrial dysfunction; and unfolded protein responses and ER stress in mice. In humans, metformin use was associated with lesser emphysema progression over time. Our results provide a rationale for clinical trials testing the efficacy of metformin in limiting emphysema progression and its systemic consequences.

Automated summary

This study demonstrated that metformin can protect against smoking-induced lung pathology in animal models, and in humans, metformin use is associated with a slower progression of emphysema. These findings suggest the potential of metformin in limiting emphysema progression and its systemic consequences.