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. 2016 Sep 22;11(9):e0162903.
doi: 10.1371/journal.pone.0162903. eCollection 2016.

Metabolic Effects Associated With ICS in Patients With COPD and Comorbid Type 2 Diabetes: A Historical Matched Cohort Study

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Free PMC article

Metabolic Effects Associated With ICS in Patients With COPD and Comorbid Type 2 Diabetes: A Historical Matched Cohort Study

David B Price et al. PLoS One. .
Free PMC article

Abstract

Background: Management guidelines for chronic obstructive pulmonary disease (COPD) recommend that inhaled corticosteroids (ICS) are prescribed to patients with the most severe symptoms. However, these guidelines have not been widely implemented by physicians, leading to widespread use of ICS in patients with mild-to-moderate COPD. Of particular concern is the potential risk of worsening diabetic control associated with ICS use. Here we investigate whether ICS therapy in patients with COPD and comorbid type 2 diabetes mellitus (T2DM) has a negative impact on diabetic control, and whether these negative effects are dose-dependent.

Methods and findings: This was a historical matched cohort study utilising primary care medical record data from two large UK databases. We selected patients aged ≥40 years with COPD and T2DM, prescribed ICS (n = 1360) or non-ICS therapy (n = 2642) between 2008 and 2012. The primary endpoint was change in HbA1c between the baseline and outcome periods. After 1:1 matching, each cohort consisted of 682 patients. Over the 12-18-month outcome period, patients prescribed ICS had significantly greater increases in HbA1c values compared with those prescribed non-ICS therapies; adjusted difference 0.16% (95% confidence interval [CI]: 0.05-0.27%) in all COPD patients, and 0.25% (95% CI: 0.10-0.40%) in mild-to-moderate COPD patients. Patients in the ICS cohort also had significantly more diabetes-related general practice visits per year and received more frequent glucose strip prescriptions, compared with those prescribed non-ICS therapies. Patients prescribed higher cumulative doses of ICS (>250 mg) had greater odds of increased HbA1c and/or receiving additional antidiabetic medication, and increased odds of being above the Quality and Outcomes Framework (QOF) target for HbA1c levels, compared with those prescribed lower cumulative doses (≤125 mg).

Conclusion: For patients with COPD and comorbid T2DM, ICS therapy may have a negative impact on diabetes control. Patients prescribed higher cumulative doses of ICS may be at greater risk of diabetes progression.

Trial registration: ENCePP ENCEPP/SDPP/6804.

Conflict of interest statement

All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: JH has received personal fees and non-financial support from Astra Zeneca and Boehringer Ingelheim, personal fees from Chiesi, Cipla and Novartis, grants from GlaxoSmithKline, and grants and personal fees from Mundipharma and Teva outside the submitted work. JWHK reports personal fees from Astra Zeneca, Boehringer Ingelheim and Novartis, grants and personal fees from GlaxoSmithKline, and grants from Zorgdraad Foundation outside the submitted work. RB reports grants and personal fees from Janssen, Boehringer Ingelheim and MSD, and personal fees from Sanofi, Astra Zeneca, Lilly, Novo Nordisk and Takeda outside the submitted work. RR reports personal fees and non-financial support from Boehringer Ingelheim, and personal fees from GlaxoSmithKline, AstraZeneca, Novartis, Teva UK, Sandoz and Almirall outside the submitted work. DP reports board membership with Aerocrine, Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Meda, Mundipharma, Napp, Novartis International, and Teva; consultancy with Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp, Novartis International, Pfizer, and Teva; grants and unrestricted funding for investigator-initiated studies from the UK National Health Service, British Lung Foundation, Aerocrine, AKL Ltd, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Eli Lilly, GlaxoSmithKline, Meda, Merck, Mundipharma, Napp, Novartis International, Orion, Pfizer, Respiratory Effectiveness Group, Takeda, Teva, and Zentiva; payments for lectures/speaking from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Meda, Merck, Mundipharma, Novartis International, Pfizer, SkyePharma, Takeda, and Teva; payment for manuscript preparation from Mundipharma and Teva; patents (planned, pending or issued) from AKL Ltd; payment for the development of educational materials from GlaxoSmithKline and Novartis; stock/stock options from AKL Ltd which produces phytopharmaceuticals; owns 80% of Research in Real Life Ltd and its subsidiary social enterprise Optimum Patient Care; received payment for travel/accommodations/meeting expenses from Aerocrine, Boehringer Ingelheim, Mundipharma, Napp, Novartis International, and Teva; funding for patient enrolment or completion of research from Almirral, Chiesi, Teva, and Zentiva; and peer reviewer for grant committees of the Medical Research Council (2014), Efficacy and Mechanism Evaluation programme (2012), HTA (2014). RM is an employee at Research in Real Life, which received a grant from Boehringer Ingelheim to conduct this research and which has conducted paid research in respiratory disease on behalf of Aerocrine, AKL Ltd, Almirall, AstraZeneca, British Lung Foundation, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp, Novartis, Orion, Respiratory Effectiveness Group, Takeda, Teva, and Zentiva. AB, HM and CD are employees at Cambridge Research Support and Observational and Pragmatic Research Institute, which are contracted by Research in Real life to provide statistical and medical writing services. Access to data from the Optimum Patient Care Research Database was co-funded by Research in Real Life Ltd. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Comparison of changes in HbA1C and diabetes-related GP visits between ICS and non-ICS cohorts.
Mild-to-moderate COPD patients identified by GOLD groups A and B. *Adjusted for number of acute courses of OCS and diagnosis of pneumonia during baseline, time between baseline and outcome HbA1c readings, and acute OCS use between index date and outcome HbA1c readings. Adjusted for diagnosis of GORD in baseline, baseline HbA1c, and duration of diabetes. Adjusted for number of acute OCS courses during baseline and time between baseline and outcome HbA1c readings. §Adjusted for baseline HbA1c and duration of diabetes.CI = confidence interval; COPD = chronic obstructive pulmonary disease; HbA1c = glycated haemoglobin; ICS = inhaled corticosteroids; GORD = gastro-oesophageal reflux disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease; GP = general practice; OCS = oral corticosteroids.
Fig 2
Fig 2. Comparison of other diabetes-related outcomes between ICS and non-ICS cohorts.
Mild-to-moderate COPD patients identified by GOLD groups A and B. *Adjusted for diagnosis of GORD in baseline, duration of diabetes, time between baseline and outcome HbA1c readings, and acute OCS use between index date and outcome HbA1c readings. Adjusted for number of allergy prescriptions and number of primary care consultations in baseline. Adjusted for baseline antidiabetic medication. §Adjusted for number of COPD consultations in baseline, time between baseline and outcome HbA1c readings, and acute OCS use between index date and outcome HbA1c readings. Adjusted for number of GP consultations in baseline. CI = confidence interval; COPD = chronic obstructive pulmonary disease; HbA1c = glycated haemoglobin; ICS = inhaled corticosteroids; GORD = gastro-oesophageal reflux disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease; GP = general practice; OCS = oral corticosteroids.
Fig 3
Fig 3. Adjusted odds ratios of the effect of cumulative ICS dose exposure and measured in fluticasone equivalents from the first prescription at the index date to the last HbA1c value in the outcome period.
*Adjusted for baseline HbA1c and acute oral corticosteroid use between index date and outcome HbA1c. Adjusted for duration of diabetes (combined first diagnosis and first prescription), baseline HbA1c and acute oral corticosteroid use between index date and outcome HbA1c. HbA1c = glycated haemoglobin; ICS = inhaled corticosteroids.

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Grant support

The analyses were funded by Boehringer Ingelheim. Access to data from the Optimum Patient Care Research Database was co-funded by Research in Real Life Ltd. The funder, Boehringer Ingelheim, had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Rafael Mares is employed by Research in Real Life Ltd., which provided support in the form of salary for author RM but did not have any additional role in the study design, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section.
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