CLINICAL RESEARCH STUDY
Inhaled Corticosteroids and the Risks of Diabetes Onset
and Progression
Samy Suissa, PhD,a,b Abbas Kezouh, PhD,a Pierre Ernst, MD, MSca,b
a
Center for Clinical Epidemiology, Lady Davis Research Institute, Jewish General Hospital, Montreal, Quebec, Canada and bthe
Department of Epidemiology and Biostatistics and Department of Medicine, McGill University, Montreal, Quebec, Canada.
ABSTRACT
BACKGROUND: Systemic corticosteroids are known to increase diabetes risk, but the effects of high-dose
inhaled corticosteroids are unknown. We assessed whether the use and dose of inhaled corticosteroids
increase the risk of diabetes onset and progression.
METHODS: We formed a new-user cohort of patients treated for respiratory disease during 1990-2005,
identified using the Quebec health insurance databases and followed through 2007 or until diabetes onset.
The subcohort treated with oral hypoglycemics was followed until diabetes progression. A nested casecontrol analysis was used to estimate the rate ratios of diabetes onset and progression associated with
current inhaled corticosteroid use, adjusted for age, sex, respiratory disease severity, and co-morbidity.
RESULTS: The cohort included 388,584 patients, of whom 30,167 had diabetes onset during 5.5 years of
follow-up (incidence rate 14.2/1000/year), and 2099 subsequently progressed from oral hypoglycemic
treatment to insulin (incidence rate 19.8/1000/year). Current use of inhaled corticosteroids was associated
with a 34% increase in the rate of diabetes (rate ratio [RR] 1.34; 95% confidence interval [CI], 1.29-1.39)
and in the rate of diabetes progression (RR 1.34; 95% CI, 1.17-1.53). The risk increases were greatest with
the highest inhaled corticosteroid doses, equivalent to fluticasone 1000 ␮g per day or more (RR 1.64; 95%
CI, 1.52-1.76 and RR 1.54; 95% CI, 1.18-2.02; respectively).
CONCLUSIONS: In patients with respiratory disease, inhaled corticosteroid use is associated with modest
increases in the risks of diabetes onset and diabetes progression. The risks are more pronounced at the
higher doses currently prescribed in the treatment of chronic obstructive pulmonary disease.
© 2010 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2010) 123, 1001-1006
KEYWORDS: Asthma; Chronic obstructive pulmonary disease; Drug safety; Glucocorticoids; Observational studies
Inhaled corticosteroids are commonly used and effective
medications for the treatment of asthma. Their indication
and effectiveness in treating chronic obstructive pulmonary
Funding: This research was funded by grants from the Canadian
Institutes of Health Research, Boehringer-Ingelheim GmbH, and the Canadian Foundation for Innovation. The sponsors had no role in the design
and conduct of the study, including data collection, management, analysis,
interpretation, or in the preparation of the manuscript.
Conflict of Interest: Samy Suissa has received speaker fees or has served
on advisory boards for AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline,
Merck, and Pfizer. Pierre Ernst has received speaker fees or
has served on advisory boards for AstraZeneca, Boehringer-Ingelheim,
GlaxoSmithKline, Merck Frosst Canada, Novartis, and Nycomed.
Authorship: All authors participated in the preparation of the manuscript.
Requests for reprints should be addressed to Samy Suissa, PhD, Centre
for Clinical Epidemiology, Jewish General Hospital, 3755 Cote Ste-Catherine, Montreal, Québec H3T 1E2, Canada.
E-mail address: [email protected]
0002-9343/$ -see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2010.06.019
disease (COPD) are controversial.1,2 While these drugs are
recommended primarily for patients with more severe
COPD who have frequent exacerbations,3 they are nevertheless widely used for this condition.2 Moreover, higher
doses of inhaled corticosteroids are commonly used in
COPD, with recent trials involving doses of 1000 ␮g of
fluticasone per day for 2-3 years.4,5 Such high doses have
been associated with significant systemic effects such as
pneumonia, glaucoma, cataracts, adrenal suppression, and
accelerated bone turnover.6-10
The question of the association between inhaled corticosteroid use and the induction and worsening of diabetes has
been rekindled recently. This issue is particularly relevant to
patients with COPD, a major cause of chronic disability
whose prevalence increases steadily with age, similarly to
type 2 diabetes.11-13 Moreover, both the prevalence and
incidence of type 2 diabetes are higher in patients with
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The American Journal of Medicine, Vol 123, No 11, November 2010
COPD.14,15 Therefore, the co-existence of these 2 chronic
These databases have been used previously to conduct epconditions among the elderly becomes important if corticoidemiological studies of the risks of glaucoma, cataracts,
steroid medications used in the treatment of COPD also are
fractures, and pneumonias associated with inhaled corticoassociated with deterioration in glycemic control.
steroids.6,7,10,21,22
Major randomized trials in COPD did not report excess
rates of adverse events of diabetes
Study Design
associated with inhaled corticosteWe first formed a populationroid use.4,5,16 These trials, while
based cohort of all people in the
CLINICAL SIGNIFICANCE
large, may not have had sufficient
population covered during 1990power to detect this excess risk.
2005 dispensed 3 or more pre● Inhaled corticosteroids are used extenObservational studies on this isscriptions for respiratory medicasively in the treatment of asthma and
sue, while reporting an excess intions in a 1-year period. Cohort
chronic obstructive pulmonary disease.
cidence of diabetes associated
entry was defined by the date of
● Inhaled corticosteroids, especially at
with the use of oral corticostethe third prescription for a respihigher doses, are associated with an
roids, did not find an excess inciratory medication. Subjects with a
dence with use.17,18 These studies,
increased risk of requiring initial drug
diagnosis of diabetes or a disconducted using data from the
therapy for diabetes.
pensed prescription for an antidi1990s, could not, however, assess
abetic drug before or on the day of
● Inhaled corticosteroids, especially at
the higher doses of inhaled corticohort entry were excluded to alhigher doses, are associated with an
costeroids currently being used. A
low the identification of new-onincreased risk of requiring insulin in parecent observational study conset diabetes. The remaining subtients treated with oral antidiabetic
ducted in the Veterans Affairs dajects were followed until the first
agents.
tabase found that inhaled corticoantidiabetic medication after costeroid use was not associated
hort entry, death, or until Decem● High doses of inhaled corticosteroids
with a change in serum glucose
ber 31, 2007. The antidiabetic
should be limited to clear guideline
concentration in patients who do
agents included oral hypoglyceindications.
not also have diabetes, but a
mics, namely sulfonylureas, metchange was observed in a doseformin, thiazolidinediones, and
response manner in patients with
insulin.
existing diabetes.19
To assess the risk of diabetes progression, we formed the
We therefore conducted a population-based cohort study
subcohort of patients dispensed a prescription for an oral
of patients treated for respiratory disease to assess whether
hypoglycemic agent during follow-up and defined as cohort
the use and the dose of inhaled corticosteroids increase the
entry the date of their first such prescription. Subjects whose
risk of new diabetes onset and, among patients who also
first antidiabetic medication was insulin were thus excluded.
have existing type 2 diabetes, whether inhaled corticosteThe remaining subjects were followed until the first preroid use leads to the need for insulin.
scription for insulin (as an indicator of disease progression)
after cohort entry, death, or until December 31, 2007.
METHODS
In view of the large sizes of the 2 cohorts, a nested
case-control analysis within each cohort was performed. For
Data Source
each case, 10 controls matched on age (within 1 year) and
We used the computerized databases of the Régie de
calendar time were selected at random from all subjects who
l’assurance maladie du Québec, the agency responsible for
entered the cohort in the same month as the case and at risk
administering the universal health insurance program of the
(alive and without the outcome of interest) on the date the
province of Québec, Canada, for all its 7 million residents.
case event occurred (index date). When fewer than 10 poThe databases contain information on demographics and all
tential controls were available for a case, all members of the
medical services rendered, along with the diagnostic code of
risk set were included as controls for that case.
th
the service (International Classification of Diseases-9 revision), for all residents of the Province. The prescription
drugs database includes outpatient prescription medications
dispensed to all people aged 65 years or older, all social
welfare recipients and, since 1996, all other residents who
choose to join the provincial drug plan. In 2002, this drug
plan was covering more than 3 million people: 545,651
individuals on welfare, 883,483 individuals aged 65 years or
more, and 1,725,331 individuals without access to private
group insurance.20 Information obtained from the Quebec
prescription claims databases has been validated previously.
Inhaled Corticosteroid Exposure
All prescriptions for inhaled corticosteroids, alone or in a
combination inhaler, dispensed before the index date were
identified and their doses obtained. These include inhaled
beclomethasone, budesonide, triamcinolone, fluticasone,
and flunisolide. All doses of inhaled corticosteroids were
converted to fluticasone equivalents according to defined
daily doses of the most recent prescription in the 30 days
before the index date, and categorized as: high (fluticasone
Suissa et al
Inhaled Corticosteroids and Diabetes Risk
1000 ␮g per day or more), moderate (500-999 ␮g per day),
and low (⬍500 ␮g per day).10
Data Analysis
Conditional logistic regression was used to estimate the
adjusted rate ratios of diabetes onset and progression associated with current use and dose of inhaled corticosteroid.
Current use was defined as a prescription in the 30 days
before the index date. The rate ratios were adjusted for age
(by design), sex, severity of respiratory disease, and comorbidity. Severity of respiratory disease was measured by
the number of dispensed prescriptions for beta-agonists,
ipratropium bromide, theophylline, and cromolyns; the
number of prescriptions for oral corticosteroids, for antibiotics; the presence of a hospitalization with a primary diagnosis of COPD or asthma; all measured in the year before
the index date. Co-morbidity included cardiac disease defined by a prescription for cardiotropes, antihypertensives,
diuretics or vasodilators; central nervous system drugs
included benzodiazepines, major tranquillizers, anticonvulsants, and drugs for parkinsonism; osteoporosis drugs included calcium, vitamin D, and bisphosphonates; antirheumatic drugs included gold salts, methotrexate, azathioprine,
hydroxychloroquine, and chloroquine. Nonsteroidal antiinflammatory drugs, anti-depressive agents, and narcotics
were considered as separate categories. All other prescriptions were regrouped.
1003
Several sensitivity analyses were performed. First, to
assess the possible contamination by concurrent oral corticosteroid use, the analysis was stratified by their use in the
year before the index date. The analysis was also stratified
according to the probability of asthma or COPD as the
underlying respiratory diagnosis. Subjects were considered
as probable COPD if they were at least 55 years old at
cohort entry, but with no mention of asthma, either as the
primary or a secondary diagnosis during hospitalization. All
other subjects were considered to have probable asthma.
RESULTS
The cohort included 388,584 patients treated with respiratory medications, after excluding 39,068 already treated for
diabetes. At cohort entry, the patients were 50.5 (⫾ 27.5)
years of age and 46% were men. The mean duration of
follow-up was 5.5 years, during which 30,167 patients initiated treatment with antidiabetic medication. Thus, the
overall incidence rate of new diabetes onset was 14.2 per
1000 per year. The subcohort of patients treated exclusively
with oral hypoglycemic agents included 27,416 subjects, of
which 2099 were subsequently given insulin during followup. Thus, the incidence rate of diabetes progression was
19.8 per 1000 per year.
Table 1 describes the characteristics of these cases of
new diabetes onset and of diabetes progression, and their
Table 1 Comparison of New Cases of Treated Diabetes and Their Matched Controls, and Cases of Diabetes Progression and Their
Matched Controls, At or In the Year Before the Index Date
New Diabetes Onset
Number
Age in years (mean ⫾ SD)
Follow-up in years (mean ⫾ SD)
Male sex (%)
COPD probable* (%)
Markers of respiratory disease severity in the
year before index date
Hospitalization for asthma or COPD (%)
Number of prescriptions (mean ⫾ SD):
Oral corticosteroids
Antibiotics
Other respiratory drugs
Treatment for other diseases in the year
before index date (%)
Cardiac drugs
Antidepressants
Central nervous system drugs
Osteoporosis drugs
NSAIDs
Narcotics
Antirheumatic drugs
Other drugs
Diabetes Progression
Cases
Controls
Cases
Controls
30,167
66.3 ⫾ 15.0
4.7 ⫾ 3.7
41.4
16.8
301,096
66.3 ⫾ 15.0
4.7 ⫾ 3.7
38.7
22.4
2,099
65.3 ⫾ 16.0
4.0 ⫾ 3.3
37.6
7.2
20,763
65.4 ⫾ 15.6
4.0 ⫾ 3.3
37.5
7.2
33.3
11.8
1.4 ⫾ 3.9
1.1 ⫾ 2.5
5.2 ⫾ 9.2
0.6 ⫾ 3.3
0.7 ⫾ 1.5
3.8 ⫾ 7.9
81.0
35.3
17.6
16.4
34.9
20.3
1.9
24.0
70.2
26.5
12.3
11.6
35.4
12.2
1.1
19.9
19.9
0.9 ⫾ 3.7
0.8 ⫾ 2.0
4.3 ⫾ 7.7
69.0
24.9
10.8
11.5
37.9
10.6
1.2
18.5
9.8
0.4 ⫾ 2.2
0.8 ⫾ 1.4
3.7 ⫾ 6.9
48.2
21.5
8.0
12.1
34.3
8.3
1.0
16.3
COPD ⫽ chronic obstructive pulmonary disease; NSAIDs ⫽ nonsteroidal anti-inflammatory drugs.
*Individuals who entered the cohort after the age of 55 years and without mention of asthma during a hospitalization.
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The American Journal of Medicine, Vol 123, No 11, November 2010
Table 2 Crude and Adjusted Rate Ratios of Newly Treated Diabetes Associated with Current
Use of Inhaled Corticosteroids among Patients Initially Free of Diabetes
Number of subjects
Inhaled corticosteroid use
No current use (%)
Current use† (%)
Low dose (%)
Medium dose (%)
High dose (%)
Cases
Controls
30,167
301,096
84.5
15.5
1.4
10.8
3.3
89.0
11.0
1.2
8.0
1.8
Crude Rate
Ratio
1.00
1.51
1.24
1.44
1.97
Adjusted*
Rate Ratio
95% CI
1.00
1.34
1.18
1.30
1.64
Reference
1.29-1.39
1.06-1.31
1.25-1.35
1.52-1.76
CI ⫽ confidence interval.
*Adjusted for all of the factors listed in Table 1.
†Current use refers to a prescription in the 30 days before the index date.
matched controls. Cases and controls were aged 66
(⫾ 15) years, and the time to treatment initiation with
antidiabetic medication was 4.7 years. The cases had
more severe respiratory disease, with a higher frequency
of asthma/COPD hospitalization and greater number of
prescriptions for respiratory drugs, including oral corticosteroids and antibiotics. The cases had slightly higher
prevalence of co-morbidity.
Table 2 shows that, after adjustment for differences in
the covariates, current use of inhaled corticosteroids was
associated with a significant 34% increase in the rate of
diabetes (rate ratio [RR] 1.34; 95% confidence interval (CI),
1.29-1.39). There was a dose-response relationship, with the
increase in the rate of diabetes greatest with the highest
doses of inhaled corticosteroids, equivalent to fluticasone
1000 ␮g per day or more (RR 1.64; 95% CI, 1.52-1.76). The
Figure displays the adjusted rate ratio as a function of the
dose, along with 95% confidence limits for the fitted doseresponse curve.
Figure Adjusted rate ratio of diabetes incidence associated
with inhaled corticosteroid use, as a function of the current
dose converted to fluticasone equivalents (in ␮g), along with
the corresponding 95% confidence limits for the fitted doseresponse curve.
Table 3 shows that the current use of inhaled corticosteroids is also associated with a 34% increase in the rate of
diabetes progression defined as a first prescription for insulin among users of oral hypoglycemic agents (RR 1.34; 95%
CI, 1.17-1.53), and a 54% increase corticosteroid dose (RR
1.54; 95% CI, 1.18-2.02). Sensitivity analyses excluding
subjects using oral corticosteroids concurrently in the year
before the index date show that the rate ratio of diabetes
onset associated with current inhaled corticosteroid use was
comparable (RR 1.28; 95% CI, 1.22-1.34). Moreover, this
rate ratio was similar in patients with probable asthma (RR
1.39; 95% CI, 1.31-1.49) or probable COPD (RR 1.28; 95%
CI, 1.22-1.34).
DISCUSSION
Using a large population-based cohort of asthma and COPD
patients, we found that the use of inhaled corticosteroids is
associated with a significant 34% increase in the risk of
incident diabetes, defined as initiation of antidiabetic medications. This risk increased with higher doses of inhaled
corticosteroids, with 1000 ␮g of fluticasone per day or
equivalent associated with 64% increase in the risk. Moreover, we found that in patients already treated for diabetes
with oral hypoglycemic agents, the risk of progression to
insulin also increased by 34% with the use of inhaled
corticosteroids, with the higher doses associated with a 54%
increase in this risk.
Clearly, systemic corticosteroids are associated with insulin resistance and hyperglycemia. Therefore, it is not
surprising that inhaled corticosteroids, especially at high
doses which have clear systemic effects,8 might result in
hyperglycemia and earlier need for therapy or its intensification. This is of concern because duration of diabetes is
associated with the likelihood of complications. While Slatore et al19 were only able to show an effect of inhaled
corticosteroids on blood sugar in patients already treated for
diabetes, this may have been due to lack of power because
they included only 1,698 subjects.19 Dendukuri et al,17 also
using the Quebec health administrative databases and with a
Suissa et al
Inhaled Corticosteroids and Diabetes Risk
1005
Table 3 Crude and Adjusted Rate Ratios of Progression to Insulin Use Associated with
Current Use of Inhaled Corticosteroids among Patients on Oral Hypoglycemic Agents
Number of subjects
Inhaled corticosteroid use
No current use (%)
Current use† (%)
Low dose (%)
Medium dose (%)
High dose (%)
Cases
Controls
2,099
20,763
84.1
15.9
0.8
11.4
3.8
89.8
10.2
0.6
7.6
2.0
Crude Rate
Ratio
1.00
1.68
1.33
1.61
2.11
Adjusted*
Rate Ratio
95% CI
1.00
1.34
1.08
1.30
1.54
Reference
1.17-1.53
0.63-1.87
1.12-1.52
1.18-2.02
CI ⫽ confidence interval.
*Adjusted for all of the factors listed in Table 1.
†Current use refers to a prescription in the 30 days before the index date.
similar design, did not find an association of diabetes, as
identified by its treatment with medications, with the dispensing of inhaled corticosteroids.17 Their study, however,
included substantially fewer subjects and covered the period
before 1997, when the predominant inhaled corticosteroid
in Quebec was low-dose beclomethasone, in comparison
with our study, which includes data up to 2007, when the
predominant exposure is moderate- and high-dose fluticasone. Interestingly, their study reported a trend, although
not significant, toward an excess risk of diabetes with highdose beclomethasone. A similar study in Ontario again did
not find a risk for inhaled corticosteroids, but this was
carried out in an earlier time period when lower doses of
less potent inhaled corticosteroids predominated.18
It is not surprising that the major randomized trials of
inhaled corticosteroids in COPD did not previously identify
excess rates of adverse events of diabetes associated with
inhaled corticosteroid use.4,5,16 With an incidence rate of
diabetes of 14.2/1000/year in this cohort of patients with
asthma or COPD, these trials, while large, did not have
sufficient power to detect the observed excess risk. We
would need a trial of 12,000 patients free of diabetes at
randomization followed for 1 year, or 4,200 patients followed for 3 years, to have sufficient power to detect a 50%
increase in the risk. To put this in perspective, the largest of
these trials, the Towards a Revolution in COPD Health
trial,4 which included over 6,000 patients over 3 years, of
which 3,000 were exposed to inhaled corticosteroids, reported an excess risk of pneumonia on the basis of a 3-year
cumulative incidence of pneumonia in the placebo group of
12.3%, in contrast to the 3-year cumulative incidence of
diabetes of 4.2% estimated from our study.
The dose-response effect of inhaled corticosteroid use
that we found on both the incidence and progression of
diabetes is particularly important in the risk-benefit equation
for patients with COPD. Indeed, while inhaled corticosteroids are very effective for the treatment of asthma, their
effectiveness in treating COPD is controversial.1,2 The fact
that inhaled corticosteroids are now commonly combined in
a single device with a long-acting bronchodilator, the latter
recommended earlier in COPD, has resulted in inhaled
corticosteroids now being used by over 70% of COPD
patients.2 Moreover, these combined medications contain
high doses of inhaled corticosteroids, as high as 1000 ␮g of
fluticasone per day.4,5 Consequently, the widespread use of
inhaled corticosteroids at higher doses in patients with
COPD, along with the elevated incidence of diabetes in this
age group and their uncertain effectiveness, can have an
impact on the risk-benefit profile of inhaled corticosteroids
in COPD.
This study has strengths and limitations. We assembled a
large population-based cohort of close to 400,000 patients
observed over 18 years. This size and long-term follow-up
of the cohort enabled the identification of a large number of
incident cases of diabetes that allowed very precise estimates of the risk associated with varying doses of inhaled
corticosteroids. While we adjusted the risk estimates for
several major confounders, there may be some residual
confounding from unmeasured covariates. Indeed, low
doses of inhaled corticosteroids were associated with a
small excess risk of diabetes onset but not progression,
although the latter analysis had insufficient power to detect
small increases in risk. However, while the risks observed at
the higher doses are consistent with the risks associated with
low doses of prednisone, the smaller risk associated with
lower doses of inhaled corticosteroids could also represent
some residual confounding. Information on obesity was not
available in the databases. Obesity may have been a confounder because it is a risk factor for diabetes; while in
asthma, obesity is associated with more severe asthma23 and
may lead to prescribing inhaled corticosteroids more frequently or at higher doses. The lack of a difference in the
risk estimates between individuals more likely to have
COPD and those more likely to have asthma suggests that
obesity was not a significant confounder because in COPD,
low body mass index, rather than obesity, is a marker of
severity.24
We defined the incidence of diabetes by a first-time
treatment with antidiabetic medications. This definition underestimates the more broad definition of diabetes measured
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The American Journal of Medicine, Vol 123, No 11, November 2010
by serum glucose levels, as these are not recorded in administrative databases. Nevertheless, our definition of diabetes is a harder measure that most likely represents the
more serious cases requiring pharmacological treatment.
Our estimates of the risk of diabetes associated with current
inhaled corticosteroid use may, therefore, be underestimated
by this under-ascertainment of the incidence of diabetes.
In conclusion, high doses of inhaled corticosteroids commonly used in patients with COPD are associated with an
increase in the risk of requiring treatment for diabetes and of
having to intensify therapy to include insulin. Therefore,
patients instituting therapy with high doses of inhaled corticosteroids should be assessed for possible hyperglycemia
and treatment with high doses of inhaled corticosteroids
limited to situations where the benefit is clear.
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