Summary of current and future treatment strategies for multimorbidity in COPD

Pulmonary effectsMultimorbid effects
Current strategies
 Smoking cessationReduction in airway inflammation
Improves respiratory symptoms and bronchial hyperresponsiveness
Prevents accelerated lung decline
Reduction of risk of cardiovascular disease and lung cancer [180]
 Exercise and pulmonary  rehabilitationDelays dynamic hyperinflation
Reduces functional breathlessness
Increases exercise capacity
Improves quality of life
Reduces anxiety and depression [181]
Increases BMI, skeletal muscle mass and improves osteoporosis [182]
 Inhaled corticosteroidsLimited reduction in airway inflammation: decrease in CD8+ T-lymphocytes in airway biopsies [183]
Reduction in exacerbations, especially in eosinophilic COPD [131]
Increased risk of pneumonia, especially in severe disease [184]
Possible reduction in cardiovascular mortality [185]
Possible reduction in systemic inflammation (CRP, TNF-α) [86]
Improvement in quality of life (in combination with bronchodilator)
 TheophyllinePossible increased inspiratory muscle strength [186]
Reduction in neutrophilic inflammation [187]
Not known
 PDE4 inhibitors, e.g.  roflumilastReduction in exacerbations and improvement in lung function in patients with chronic bronchitis, FEV1 <50% and history of frequent exacerbationsPrevention of bone loss and increase in skeletal muscle mass (in a murine model) [188]
Cardiovascular-targeted treatments
 StatinsMay reduce exacerbations [189]Reduction in cardiovascular risk [190]
Reduction in oxidative stress and inflammation [191]
 ACE inhibitors/ARBReduction in exacerbations [192]
Decrease in hyperinflation [193]
May improve survival (in those with cardiovascular risk)
 β-BlockersReduction in exacerbations [194]Reduction in mortality after myocardial infarction [195] and in heart failure [196]
Reduction in oxidative stress [197]
Improved exercise capacity [198]
Future strategies
 Metformin (targeting  PI3K-AKT-mTOR pathway)May improve respiratory symptoms and reduce hospitalisations [199]Possible reduction in mortality in COPD patients with diabetes [200]
 Resveratrol (plant-based  antioxidant)Anti-inflammatory in lung epithelial cells [201]Possible cardioprotective effects [202]
 Losmapimod (p38 MAPK  inhibitor)No effect on respiratory symptoms or lung function, but a trend towards reduction in exacerbations [203]Not yet determined; possible effect on arterial inflammation
 NF-κB inhibitors, e.g. IκB  kinase inhibitorsNot yet determined; possible effects on exacerbations given role in activating inflammatory signalling in the COPD lung [204]Not yet determined; possible effects on skeletal muscle wasting [205], cardiovascular disease, lung cancer, osteoporosis and diabetes [206]
 Antioxidants, e.g. Nrf2  activators, NOX4  inhibitorsNot yet determined; possible reduction in inflammation and reversal of corticosteroid resistanceNot yet determined; issues with side-effect profile
 Mesenchymal stem cell EVsNot yet determined; initial trials failed to show benefit [207]Not yet determined; possibly neuroprotective [208], cardioprotective [209] and anti-inflammatory [210]

PDE4: phosphodiesterase-4; ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blockers; PI3K: phosphatidylinositol 3-kinase; AKT: also known as protein kinase B; mTOR: mechanistic target of rapamycin; MAPK: p38 mitogen-activated protein kinase; IκB: inhibitor of NF-κB; Nrf2: nuclear factor erythroid 2-related factor 2; NOX: NADPH oxidase; EVs: extracellular vesicles; BMI: body mass index; CRP: C-reactive protein; TNF: tumour necrosis factor; FEV1: forced expiratory volume in 1 s.