An example of a new indication for an old drug is that of inhaled corticosteroids in chronic obstructive pulmonary disease (COPD) and metformin, an anti-diabetic medication, which has been receiving much attention recently as a potential anti-cancer agent, primarily on the basis of several observational studies Inhibitors,research,lifescience,medical that reported impressive reductions in the incidence of and mortality from cancer. These observational

studies formed the impetus for the conduct of major large-scale randomized trials. In this paper, we show that the spectacular effects reported in many of the observational studies that have been conducted in this context are the result of time-related biases, particularly immortal time bias which tends to exaggerate the benefits observed with a drug. We also show how the studies could have avoided this bias, and the ones that did actually reported null effects. With this knowledge, it is unlikely Inhibitors,research,lifescience,medical that randomized trials would have been conducted. INHALED CORTICOSTEROIDS IN COPD Chronic obstructive pulmonary disease, a disease that encompasses emphysema, chronic obstructive bronchitis, and small airway obstruction, is characterized by largely irreversible airflow obstruction.10 It currently affects Inhibitors,research,lifescience,medical around 10% of the population over the age of 40 years

and has recently check details become the third leading cause of death in the US.11,12 The pharmacological treatment of COPD has generally consisted of bronchodilators. However, because of the presence of inflammation in COPD, inhaled corticosteroids, which had been shown to be highly effective for the treatment of asthma, were readily adopted in COPD in the 1980s despite the fact Inhibitors,research,lifescience,medical that no randomized controlled trials had yet evaluated their effectiveness in this indication. The earliest randomized controlled trials to evaluate inhaled

corticosteroids in the treatment of COPD were only published in the late 1990s. The first seven trials Inhibitors,research,lifescience,medical found no improvement in the decline of lung function over time and, except for the last two trials, found no reduction in exacerbation rates Montelukast Sodium with various inhaled corticosteroids (ICS) compared with placebo, over periods ranging from 6 months to 3 years.13–19 In the early 2000s, the next wave of randomized controlled trials all involved the evaluation of inhaled corticosteroids combined with a long-acting beta-agonist.20–25 Most of these trials reported significant effects on lung function and reductions in exacerbation rates with the combination therapy, while the effects of inhaled corticosteroids alone were equivocal. Thus, the totality of these trials can be concluded to imply that any effectiveness of these medications is driven primarily by the long-acting beta-agonist component.