Metformin in severe exacerbations of chronic obstructive pulmonary disease: a randomised controlled trial

Abstract

Background: Severe exacerbations of COPD are commonly associated with hyperglycaemia, which predicts adverse outcomes. Metformin is a well-established anti-hyperglycaemic agent in diabetes mellitus, possibly augmented with anti-inflammatory effects, but its effects in COPD are unknown. We investigated accelerated metformin therapy in severe COPD exacerbations, primarily to confirm or refute an anti-hyperglycaemic effect, and secondarily to explore its effects on inflammation and clinical outcome.

Methods: This was a multicentre, randomised, double-blind, placebo-controlled trial testing accelerated metformin therapy in non-diabetic patients, aged ≥35 years, hospitalised for COPD exacerbations. Participants were assigned in a 2:1 ratio to 1 month of metformin therapy, escalated rapidly to 2 g/day, or matched placebo. The primary end point was mean in-hospital blood glucose concentration. Secondary end points included the concentrations of fructosamine and C reactive protein (CRP), and scores on the COPD Assessment Test and Exacerbations of Chronic Pulmonary Disease Tool.

Results: 52 participants (mean (±SD) age 67±9 years) were randomised (34 to metformin, 18 to placebo). All were included in the primary end point analysis. The mean blood glucose concentrations in the metformin and placebo groups were 7.1±0.9 and 8.0±3.3 mmol/L, respectively (difference -0.9 mmol/L, 95% CI -2.1 to +0.3; p=0.273). No significant between-group differences were observed on any of the secondary end points. Adverse reactions, particularly gastrointestinal effects, were more common in metformin-treated participants.

Conclusion: Metformin did not ameliorate elevations in blood glucose concentration among non-diabetic patients admitted to hospital for COPD exacerbations, and had no detectable effect on CRP or clinical outcomes.

Trial registration number: ISRCTN66148745 and NCT01247870.

Keywords: COPD Exacerbations; COPD Pharmacology.

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Figures

Figure 1

Flow diagram showing patient disposition. NYHA, New York Heart Association.

Figure 2

Plot showing mean in-hospital capillary blood glucose concentrations. Individual participant means are indicated by shaded circles, and group level means are indicated by solid circles with error bars denoting SD. The difference between the metformin and placebo groups was −0.9 mmol/L (95% CI −2.1 to +0.3; p=0.273). In a sensitivity analysis specified after data collection but before unblinding, in which an extreme outlier was excluded (mean blood glucose concentration 20.2 mmol/L), the difference between groups was −0.2 mmol/L (95% CI −0.8 to +0.45; p=0.566).

Figure 3

Box and whiskers plot showing high-sensitivity C reactive protein concentration. Medians are denoted by horizontal bars, IQRs by boxes and ranges by whiskers, save for any outliers which are denoted by circles. The lower limit of detection for the assay is indicated by a dashed line (0.3 mg/L).There were no significant differences in the absolute concentrations between the metformin and placebo groups at any time points.

Figure 4

COPD Assessment Test (CAT) scores. CAT scores are on a 40-point scale, with higher scores indicating worse COPD-related health status. Medians are denoted by horizontal bars, IQRs by boxes and ranges by whiskers, save for any outliers which are indicated as circles. There were no significant differences between the groups at any time point.

Figure 5

Exacerbations of Chronic Pulmonary Disease Tool (EXACT) scores. EXACT scores are on a 100-point logit scale, with higher scores indicating worse symptoms. Error bars indicate SDs. There were no significant differences between the groups at the three prospectively defined time points for comparison (indicated by solid markers). Day 1 was defined as the first day on which the study medication was administered.