NPC Archive Item: Inhaled corticosteroids and the risk of diabetes

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8th February 2011

A Canadian cohort study identified that patients treated for respiratory disease using inhaled corticosteroids (ICS) over a period of 5.5 years were, on average, at a 34% increased risk of both diabetes onset and diabetes progression compared with patients not treated with ICS. The risk increased with increasing dose of ICS. Patients treated with high doses of ICS, equivalent to fluticasone 1000microgram/day or more, had, on average, a 64% increased risk of developing diabetes compared with patients not treated with ICS.

Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.

Prescribers should follow the British guideline for the management of asthma with regard to the use of ICS in patients with asthma. The dose of ICS should be titrated to the lowest dose at which effective control is maintained. In COPD, ICS should only be used only in combination with a long-acting beta-agonist and only  in accordance with the NICE guideline for COPD.

Systemic side effects are of crucial importance when considering the benefits and risks for individuals with asthma or COPD for whom ICS are being considered, and healthcare professionals should be prepared to discuss these with patients. Pending further data and/or formal consideration by the regulatory authorities, among the other side effects of ICS (see background section below), physicians need to be aware of the potential for ICS to increase the risk of, and be vigilant for, the development of diabetes, particularly if used at high doses for prolonged periods.

What is the background to this?
Prolonged use of high doses of ICS (as with the use of oral corticosteroids) carries a risk of systemic side effects (e.g. adrenal suppression or crisis, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma) and a range of psychological or behavioural effects (e.g. psychomotor hyperactivity, sleep disorders, anxiety, depression, and aggression, particularly in children). Healthcare professionals are reminded when treating patients with ICS in COPD to remain vigilant for the development of pneumonia and other infections of the lower respiratory tract (i.e. bronchitis). Because of the risk of systemic side effects, patients who require prolonged high-dose ICS should be issued with a steroid treatment card.

Systemic corticosteroids are known to increase diabetes risk, but the effects of inhaled corticosteroids on the development of diabetes are less certain. This cohort study examined the relationship between the use and dose of ICS in a large population of Canadian patients with asthma and COPD and the onset and progression of diabetes, as assessed by a prescription of an oral hypoglycaemic agent and subsequent prescription of insulin, respectively.

What does this study claim?
This study found that the overall incidence rate of new diabetes onset during the period of follow up was about 1.4%/year. Current use of ICS was associated with a statistically significant 34% increase in the rate of diabetes (rate ratio [RR] 1.34, 95% confidence interval [CI], 1.29 to 1.39) and in the rate of diabetes progression (RR 1.34, 95% CI 1.17 to 1.53). The rates of onset were similar in patients with probable asthma or probable COPD. The risk increases were greatest with the highest inhaled corticosteroid doses, equivalent to fluticasone 1000microgram/day or more (RR 1.64, 95% CI 1.52 to 1.76 and RR 1.54; 95% CI 1.18 to 2.02; respectively).

How does this relate to other studies?
Major randomised controlled trials of ICS in COPD have not identified excess rates of adverse events of diabetes associated with ICS use. However, this is not surprising as they would have been underpowered to detect a statistically significant difference, given the incidence rate of diabetes (1.4% per year) found in this study and the magnitude of the increased risk associated with ICS use. An earlier, smaller observational study to the present study using the same database, found no significant association with the use of inhaled corticosteroids and diabetes onset, although this covered a period before 1997, when the predominant ICS was beclometasone. In contrast, the present study covered the period to 2007, when fluticasone was the predominant ICS used.

So what?
Although the use of oral corticosteroids is known to be associated with increased risk of diabetes, this appears to be the first study that demonstrates a significant association between diabetes onset and the use of ICS. However, this result is not surprising given that other systemic side effects, mirroring those of oral corticosteroids, are well known. It has previously been estimated that an inhaled dose of 1000micrograms of fluticasone has approximately equivalent adrenal suppressive effects as a systemic dose of 10mg of oral prednisolone. There is, however, considerable inter-individual susceptibility to systemic effects of inhaled corticosteroids, so that it is difficult to predict whether systemic effects will develop in an individual at a given dose of ICS. High doses of ICS have also been associated with lower respiratory tract infections, particularly pneumonia, in elderly patients with COPD.

This study is limited by its observational nature: the analysis was subject to the influence of many confounders, and not all of them (e.g. obesity) were able to be taken into account. However, the association is strengthened by the dose relationship shown between ICS dose and risk of diabetes.

The potential for ICS to increase risk of diabetes is another possible adverse effect to consider when reviewing the risks and benefits of ICS with patients, particularly if high doses are being considered for prolonged period. Based on an estimated baseline risk of 1.36%/year, and an increased relative risk of 64%, we calculate that the number needed to harm (NNH) for patients taking high-dose ICS is approximately 21 over 5.5 years. Or putting it another way, if 21 patients are treated with high-dose corticosteroids for 5.5 years, one of them will develop diabetes requiring drug treatment who otherwise would not have done if they had not been prescribed ICS.

Study details

Suissa S, et al. Inhaled corticosteroids and the risks of diabetes onset and progression. Am J Med 2010;123:1001–6

Nested case-control analysis of a cohort of patients treated for respiratory disease during 1990-2005, identified using the Quebec health insurance databases; followed through 2007 or until diabetes onset.

388,584 patients (mean age 50.5 years, 46% men), of whom 30,167 had diabetes onset (defined as initiation of treatment with a diabetes medication) during 5.5 years of follow-up, and 2,099 subsequently progressed from oral hypoglycemic treatment to insulin.

Intervention and comparison
Conditional logistic regression analysis was used to estimate the adjusted RR of diabetes onset and progression associated with current use (prescription within 30 days of index date and dose of ICS). RRs were adjusted for age, sex, severity of respiratory disease, and comorbidity.

Outcomes and results
This study found that the overall incidence rate of new diabetes onset during the period of follow up was 1.42%/year. The incidence rate of diabetes progression was 1.98%/year. Current use of inhaled corticosteroids was associated with a statistically significant 34% increase in the rate of diabetes (RR 1.34, 95% CI 1.29 to 1.39) and in the rate of diabetes progression (RR 1.34, 95% CI 1.17 to 1.53). Sensitivity analyses excluding subjects using oral corticosteroids concurrently in the year before index date show that the RR of diabetes onset associated with current ICS use was similar (RR 1.28, 95%CI 1.22 to 1.34). The rate of diabetes onset was similar between those with probable asthma (RR 1.39, 95%CI 1.31 to 1.49) and probable COPD (RR 1.28, 95%CI 1.22 to 1.34). The risk of diabetes onset increased with higher inhaled corticosteroid dose — low dose (equivalent to fluticasone <500microgram/day) RR 1.18, 95%CI 1.06 to 1.31); medium dose (equivalent to fluticasone 500 to 999microgram/day) RR 1.30, 95%CI 1.25 to 1.35); high dose (equivalent to fluticasone ≥1000microgram/day) RR 1.64, 95% CI 1.52 to 1.76. The risk of diabetes progression increased with higher inhaled corticosteroid dose — low dose RR 1.08 (95%CI 0.63 to 1.87); medium dose RR 1.30 (95%CI 1.12 to 1.52); high dose RR 1.54 (95% CI 1.18 to 2.02).

Funded by grants from the Canadian Institutes of Health Research, Boehringer-Ingelheim GmbH, and the Canadian Foundation for Innovation.

More information on COPD and asthma can be found on the respiratory tract section of NPC.

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