Andrew W. Hitchings

Safety of Metformin in Patients with Chronic Obstructive Pulmonary Disease and Type 2 Diabetes Mellitus

Abstract Type 2 diabetes mellitus (T2DM) is commonly associated with chronic obstructive pulmonary disease (COPD). Metformin is a valuable treatment for T2DM, and may offer additional benefits in COPD. However, due to its rare association with lactic acidosis, its safety in COPD is uncertain. We retrospectively identified patients with T2DM who had been admitted to hospital for COPD exacerbations. We compared those who were taking metformin with those who were not, with respect to their lactate concentration (primary endpoint) and survival (secondary endpoint). The study cohort (n = 130) had a mean (±standard deviation) age of 73.0 ± 9.8 years and 47 (36%) were female. Arterial blood gases were recorded in 120 cases: 88 (73%) were hypoxemic, 45 (38%) were in respiratory failure and 33 (28%) had respiratory acidosis. The 51 patients (39%) in the metformin group had a median (interquartile range) lactate concentration of 1.45 mmol/L (1.10–2.05) versus 1.10 mmol/L (0.80–1.50) in the non-metformin group (p = 0.012). Median survival was 5.2 years (95% CI 4.5–5.8) versus 1.9 years (1.1–2.6), respectively (hazard ratio 0.57; 95% CI 0.35–0.94). This remained significant in a multivariate model adjusted for measurable confounders. In conclusion, among patients with COPD at high risk for lactate accumulation, metformin therapy was associated with a minor elevation of lactate concentration of doubtful clinical significance. Metformin was associated with a survival benefit, but this must be interpreted cautiously due to possible effects from unmeasured confounders. Viewed collectively, the results suggest that COPD should not present a barrier to the investigational or clinical use of metformin.

Making medicines evergreen.

Andrew Hitchings, Emma Baker, and Teck Khong examine how drug companies maximise profits after patents expire and show why regulatory agencies, policy makers, and prescribers need to be alert to the use of these techniques

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

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.

Dissemination and uptake of a new treatment pathway for paracetamol poisoning in the UK: a survey of healthcare professionals

AIMS On 3 September 2012, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) notified healthcare professionals of immediate changes to the intravenous acetylcysteine license terms, altering the treatment pathway for paracetamol poisoning. We sought to evaluate awareness of this amongst healthcare professionals. METHODS We surveyed doctors, nurses and pharmacists in the 1-12 week period following the implementation date. RESULTS Forty-four individuals completed the survey in paper form (response rate 86%) and 220 in electronic form (response rate unknown). The resulting sample of 264 individuals was drawn from 41 institutions, and included 143 doctors, 58 pharmacists and 50 nurses. Of these individuals, 157 (59%) were aware of the changes, and 133 (50%) had adopted them in practice. Awareness differed between healthcare professions (P = 0.001) and specialties (P = 0.002). For respondents aware of the changes, the main sources of information were alerts issued internally (reported by 57%), from the MHRA (25%) and from other professional bodies (24%). The proportion of individuals who reported receiving practical implementation instructions (e.g. a protocol) was higher among respondents who had changed their practice than for those who had not (86 vs. 25%, respectively; P < 0.001). CONCLUSIONS Less than two-thirds of healthcare professionals in specialties managing patients with paracetamol poisoning were aware of important changes to its treatment pathway in the 12 weeks after they took effect, and only half had adopted them in practice. Alternative communication strategies should be explored to improve dissemination of similar information from the MHRA and other medicines regulators in the future.

Avoiding unnecessary arterial blood sampling in COPD exacerbations: a stab in the right direction

Hospital admissions for exacerbations are major events in the lives of people with COPD. The prognosis for such patients is grim. Around one in seven will die within 3 months of admission, and fewer than half will still be alive at 5 years.1 ,2 The symptoms they experience are frightening and unpleasant,3 their quality of life is reduced4 and the restriction in their physical activity, which may persist for weeks after the onset of symptoms, increases the risk that they will become housebound.5 In comparison with other medical emergencies, such as myocardial infarction and stroke, progress in improving the management of COPD exacerbations has been depressingly slow. Arguably, the last major advance was the introduction of non-invasive ventilation, which took place sometime in the latter part of the last century. Against this backdrop, it is vital that, as a clinical and research community, we should tenaciously pursue all opportunities to improve the experience for these patients. In doing this, we must reflect critically on our existing practice and the pain and burdens it may present for those who endure it. In this issue of Thorax , McKeever et al 6 do just this, by questioning the need for an investigation that many of us would consider almost sacrilegious to omit: the arterial blood gas. Learning and refining the technique of arterial blood sampling is a rite of passage for medical students, junior doctors and increasingly other healthcare professionals. Evidence of their efforts is perhaps most conspicuous among the inpatient COPD population, where masses of haphazardly taped cotton-wool balls adorn the increasingly purpuric wrists of these unfortunate individuals. As McKeever et al have observed, the pain associated with arterial blood …

The ‘top 100’ drugs and classes in England: an updated ‘starter formulary’ for trainee prescribers

Prescribing is a complex skill required of doctors and, increasingly, other healthcare professionals. Use of a personal formulary can help to develop this skill. In 2006–9, we developed a core list of the 100 most commonly prescribed drugs. Our aim in the present study was to update this ‘starter formulary’ to ensure its continued relevance for prescriber training.

Handling missing items in the Exacerbations of Chronic Pulmonary Disease Tool

The Exacerbations of Chronic Pulmonary Disease Tool (EXACT) is a 14-item, self-administered daily symptom diary designed to identify and characterise exacerbations of chronic obstructive pulmonary disease (COPD). It provides a reliable, valid and standardised measure of exacerbation symptoms, and is sensitive to changes during recovery [1]. Scores are expressed on a 100-point scale, with higher values indicating worse symptoms or health state. In addition, the EXACT-derived E-RS (EXACT Respiratory Symptoms) provides valid daily COPD symptom scores [2, 3]. Electronic administration is recommended and has several advantages, notably in preventing item omission [4]. However, the expense of electronic solutions may prove prohibitive, particularly in noncommercial studies, when a pen-and-paper version may be used instead. In this context, it is important to have a method to deal with missing items. This is yet to be established. Within certain limits, missing items in the EXACT instrument can be imputed from the remaining answered items http://ow.ly/4mJQzP