Short-Term Risk for Stroke Is Doubled in Persons With
Newly Treated Type 2 Diabetes Compared With Persons
Without Diabetes
A Population-Based Cohort Study
Thomas Jeerakathil, MD, MSc; Jeffrey A. Johnson, PhD;
Scot H. Simpson, PharmD, MSc; Sumit R. Majumdar, MD, MPH
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Background and Purpose—Cardiovascular risk factors are suboptimally treated in diabetes, possibly because of the
impression that there is a long delay between diagnosis and the development of macrovascular complications such as
stroke. We determined the incidence of stroke in people newly treated for type 2 diabetes.
Methods—We conducted an inception cohort study with the use of linked administrative databases from Saskatchewan
Health. Subjects entered the type 2 diabetes cohort on receipt of their first prescription for an oral antidiabetic drug. We
defined incident stroke as any hospital admission with International Classification of Diseases, Ninth Revision, codes
430 to 438 inclusive. Age-standardized incidence rates were compared between the diabetes cohort and the general
population.
Results—There were 12 272 subjects in the diabetes cohort, the mean⫾SD age was 64⫾13.6 years, and 55% were male.
During a mean 5-year follow-up, 9.1% of the diabetes cohort had a stroke. The age-standardized incidence rate for stroke
was 642 per 100 000 person-years in subjects with diabetes, compared with 313 per 100 000 person-years in the general
population (rate ratio⫽2.1, 95% CI⫽1.8 to 2.3). The relative short-term risk for stroke in the diabetes cohort compared
with the general population ranged from 1.8 (95%⫽CI 1.6 to 1.9) in persons ⬎75 years to 5.6 (95% CI⫽2.5 to 9.3) in
the 30- to 44-year category.
Conclusions—The risk of stroke is high within 5 years of treatment for type 2 diabetes and more than double the rate for
the general population. This further supports the need for aggressive early cardiovascular risk factor management in type
2 diabetes. (Stroke. 2007;38:000-000.)
Key Words: type 2 diabetes mellitus 䡲 stroke incidence 䡲 follow-up study
T
prevalence of stroke was 1.6% and the prevalence of coronary
disease was 6.3%.7 The cross-sectional DICE study reported
“prior stroke” to be present in 3% to 5% of persons with
diabetes when assessed within 5 years after diagnosis.8
Neither study, however, provided information on the incidence of stroke after the onset of diabetes.
An understanding of the short-term risk for stroke, in both
absolute and relative terms, may be relevant, considering the
widely documented “care gaps” present in the treatment of
cardiovascular risk factors in patients with type 2 diabetes.8 –13 It is possible that this undertreatment of atherosclerotic risk may be the result of a prevailing attitude among
physicians and patients that the cardiovascular complications
of diabetes occur long after diagnosis (ie, 10 to 15 years) or
ype 2 diabetes mellitus is associated with a 2- to 3-fold
increase in the risk of stroke.1– 6 Some of these observational studies have reported stroke risk for periods of 10 or
more years, but there are few data on the absolute or relative
stroke risk in the first 4 to 5 years (ie, in the short term) after
diagnosis of type 2 diabetes. In fact, the widely cited UKPDS
risk model specifically excluded stroke events that occurred
during this short-term period.7 In addition, the data for this
model were drawn from observations taken from trial participants, rather than a more applicable general diabetic population. Limited data do exist about the prevalence of stroke at
the time of diagnosis of type 2 diabetes. The DIADEM study,
which examined 5572 persons with newly diagnosed diabetes
recruited from primary care offices, reported that the point
Received December 26, 2006; accepted January 16, 2007.
From the Division of Neurology (T.J.); the Department of Medicine, Faculty of Medicine and Dentistry (T.J., S.R.M., J.A.J.); the School of Public
Health (J.A.J., S.R.M.), and the Faculty of Pharmacy and Pharmaceutical Services (S.H.S.), University of Alberta, and the Institute of Health Economics
(J.A.J., S.R.M., S.H.S.), Edmonton, Canada.
This study was based in part on anonymized data provided by the Saskatchewan Department of Health. The interpretation and conclusions contained
herein do not necessarily represent those of the Government of Saskatchewan or the Saskatchewan Department of Health.
Correspondence and reprint requests to Dr Thomas Jeerakathil, 2E3.34 WC Mackenzie Centre, 8440 112th St, Edmonton, Alberta, Canada, T6G 2B7.
E-mail [email protected]
© 2007 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/STROKEAHA.106.481390
1
2
Stroke
June 2007
that glycemic control (rather than management of blood
pressure or high cholesterol) is paramount. Furthermore,
early stroke risk may be important for both physicians and
patients, given that the general public is more concerned with
having a major stroke than with having a myocardial infarction and that patients attach more value to preventing events
that occur in the short term.14 –16
Thus, an understanding of the short-term risk for stroke in
people with type 2 diabetes may improve the motivation of
both physicians and patients to adhere to proven therapies to
lower stroke risk in this group of subjects.15,16 Therefore, we
investigated the short-term risk for stroke in all patients with
newly treated type 2 diabetes from the population of
Saskatchewan, Canada.
Subjects and Methods
Setting and Sources of Data
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This study used linkable administrative health databases of the
province of Saskatchewan, which has a population of ⬇1 million
people.17 Health care within the province is publicly funded for all
residents, and all are assigned a personal healthcare number. The
provincial databases include a population registry with basic demographic data on all registered beneficiaries. The hospital services
database contains discharge codes for all hospital separations, as well
as information on discharge destination. A vital statistics database
captures deaths and causes of death. The pharmacy prescription
database records medication name, strength, quantity, and dispensation date for the ⬇91% of provincial residents who are eligible for
prescription drug coverage.
Diabetes Cohort
As in previous studies, registered beneficiaries of Saskatchewan
Health ⱖ30 years old were included in the cohort if they had a
dispensation claim for a sulfonylurea or metformin during the index
period of 1991 to 1996.18 We defined persons as newly treated type
2 diabetics if there were no other dispensations for antidiabetic
drugs, including insulin, in the year before the index dispensation.18
We followed up the subjects until they moved from the province,
died, or December 31, 1999, when the monitoring period concluded.
These criteria identified 12 272 subjects. Information was available
on a number of covariates, including age, sex, and medications.
General Population Comparison Group
The number of stroke hospitalizations (see subsequent section for
definition) per year, by age and sex category, for the entire province
of Saskatchewan is publicly available from the Canadian Institute
for Health Information.19 Similarly, Statistics Canada reports the
population size per year, by age and sex category, for the entire
province.20 This allows population-based stroke rates to be calculated for the province and subsequently, age- and sex-standardized
comparisons of stroke rates between the study group and the general
population.
Outcomes
Information on stroke hospitalizations was available from the hospital services database using International Classification of Diseases,
Ninth Revision, codes 430 to 438 inclusive as the primary discharge
diagnosis. We considered only the first stroke-related event that
occurred in the diabetes cohort in our analyses, although all stroke
hospitalizations were included in the population comparator group,
including recurrent events. These diagnostic codes have been previously validated for stroke-related events in Saskatchewan.21
Analysis
We determined the proportion of subjects in the diabetes cohort who
had a stroke-related hospitalization. The occurrence of stroke was
also expressed as an incidence rate with person-years of follow-up as
the denominator. We also produced Kaplan–Meier survival curves
for stroke occurrence for our diabetes cohort. We then compared
stroke rates in our population-based sample of people with type 2
diabetes with the independently ascertained and published stroke
rates from the general population of Saskatchewan. To do so, we
determined the population of Saskatchewan as of July 1, 1996,
according to published data from Statistics Canada.20 From the
discharge abstracts database, we obtained the number of stroke
hospitalizations that occurred in fiscal year 1996 by age category.19
We age-standardized stroke rates from our cohort to the 1996 general
population of Saskatchewan by the direct method and then determined rate ratios for stroke for our cohort compared with the general
population. To ensure that our rate ratios remained stable for
reference population samples from different years, we also determined rate ratios for stroke between our study sample and the general
population samples of the population of Saskatchewan from the
years 1994 and 1999.19,20 All analyses were performed with SAS
version 9.1 (SAS Institute, Cary, NC).
Results
There were 12 272 persons in the diabetes cohort. Their mean
age was 64 years (range, 30 to 105; SD⫽13.6) and 55% were
male. There was a mean 5.1 years of follow-up (range, 0 to 9;
SD⫽2.16), providing a total of 62 808 person-years of
follow-up. Antidiabetic medication use during the course of
follow-up was as follows: sulfonylurea monotherapy, 4424
(36%); metformin monotherapy, 1547 (12%); metformin and
sulfonylurea combination, 4858 (40%); and combination
therapy with insulin, 1443 (12%). There were 990 240
persons in the census population of Saskatchewan in 1996
(49% male).
Admission for any stroke-related diagnosis occurred in
9.1% (1122/12 272) of the diabetes cohort, and 21.9% (2688/
12 272) died during the 5 years of follow-up (the Table).
There were 1122 individuals who had a first admission for a
stroke-related diagnosis, yielding a rate of 1786 strokes per
100 000 person-years. This figure compares with 3099
strokes for 990 240 person-years in the general population.
After age standardization, the stroke rate was 642 per 100 000
person-years for those with newly treated type 2 diabetes
compared with 313 per 100 000 person-years for the general
population. The rate ratio (95% CI) for stroke was 2.1 (95%
CI⫽1.8 to 2.3) for those in the diabetes cohort compared with
the general population. Age-standardized stroke rates increased markedly with age and were higher for the diabetes
cohort than for the general population (Figure 1). The
magnitude of elevated risk for stroke in persons with diabetes
compared with the general population was greater for
younger subjects than older subjects (the Table 1 and Figure
2). For example, in the 30- to 44-year age category, persons
with newly treated diabetes had a rate ratio for stroke of 5.6
(95% CI⫽2.5 to 9.3) compared with individuals of similar
age in the general population. However, the absolute risk for
stroke was much higher in older persons with diabetes
(18.7%) compared with younger persons with diabetes
(1.0%). We found similar or greater rate ratios for stroke
when we age-standardized our cohort to the general population for the year 1994 (rate ratio⫽2.0, 95% CI⫽1.8 to 2.2) or
1999 (rate ratio⫽2.5, 95% CI⫽2.3 to 2.8) and compared
stroke rates in the diabetes cohort with those of the general
population in those years. Hospitalization for stroke occurred
Jeerakathil et al
Stroke Risk Is Doubled in New Type 2 Diabetes
3
Short-Term Stroke Risk by Age Category in Persons With Diabetes Compared With the General Population
of Saskatchewan, Canada, in 1996
Subgroup
All combined
Age 30–44 y
Age 45–59 y
Age 60–74 y
Age ⱖ75 y
Group
No. of Stroke Admissions
(% of Total n in Category)
Person-Years of
Follow-Up
Stroke Rate per
100 000 Person-Years
Rate Ratio (95% CI)
DM cohort
1122 (9.14)
62 808.06
642.08†
2.1 (1.8, 2.3)
GP
3099§
990 240
312.95
DM cohort
12 (0.98)
GP
72§
DM cohort
110 (3.31)
GP
248§
DM cohort
476 (9.67)
GP
993§
DM cohort
GP
Males
DM cohort
GP
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Females
DM cohort
GP
524 (18.65)
1774§
640 (9.45)
1641§
482 (8.74)
1458§
6749.65
226 285
177.79
5.6 (2.5, 9.3)
31.82
18 336.14
599.91
148 400
167.12
26 005.43
1830.39
115 980
856.18
11 709.17
4475.13
69 625
2547.94
34 251.26
635.95‡
489 430
335.29
28 556.8
631.28‡
500 805
291.13
3.6 (2.8, 4.5)
2.1 (1.9, 2.4)
1.8 (1.6, 1.9)
1.9 (1.6, 2.2)
2.2 (1.8, 2.5)
DM (diabetes mellitus) cohort refers to the group of 12 272 persons with newly treated diabetes. GP refers to the general population
of the province of Saskatchewan in 1996.
†Age-standardized to the entire control population.
‡Age-standardized to the male or female control population.
§Stroke hospitalizations for the control population were available as population rates with a denominator of person-years; therefore,
it was not appropriate or possible to report the percentage of persons with stroke for the control population.
in a lower proportion of women (8.7%) than men (9.5%);
however, women had a slightly higher relative risk for stroke
compared with the general population than men (the Table).
The Kaplan–Meier survival curve for persons with diabetes
shows that stroke hospitalizations increased steadily in the
first 5 years and then more precipitously afterward, with
nearly 19% of those remaining in the diabetes cohort having
a stroke hospitalization by the 8-year mark (Figure 3).
Discussion
We found that persons newly treated for type 2 diabetes were
at a substantially elevated short-term risk for stroke compared
with individuals in the general population, with an almost
10% absolute risk within 5 years. The relative risk of stroke
within the diabetes cohort itself was greater for younger
persons than for older persons. On the other hand, the
absolute risk for stroke increased considerably with age,
ranging from ⬇1% in 5 years for those 30 to 44 years old to
almost 20% for those ⬎75 years of age. To our knowledge,
ours is the first study to specifically examine stroke-related
outcomes soon after the diagnosis of and initiation of treatment for type 2 diabetes. Given the number of evidence-based
treatments available for the prevention of stroke, these data
should be useful for both patients with new-onset diabetes
and their healthcare providers.22
The strengths of this study include a large populationbased sample with little loss to follow-up, universal healthcare coverage, and databases that have been validated in
general and for stroke specifically. Our study also has a
number of limitations. First, persons with “diet-controlled”
Figure 1. Age-standardized stroke hospitalization rates for the cohort with newly
treated type 2 diabetes and the 1996
general population of Saskatchewan.
4
Stroke
June 2007
Figure 2. Rate ratios and 95% CIs for stroke hospitalization in
the cohort with newly treated type 2 diabetes compared with
the 1996 general population of Saskatchewan by 15-year age
category. The relative risk for stroke is higher in younger subjects compared with older subjects.
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diabetes were not captured. If these individuals are at an
earlier stage in their disease process, it is conceivable that
they might be at lower risk for stroke than our results would
indicate. Conversely, there is evidence that patients with
diet-controlled type 2 diabetes may have poorer control of
serum glucose and cardiovascular risk factors than those
treated with hypoglycemic agents or insulin.23
Second, we were unable to exclude with certainty those
patients who had experienced a stroke in the remote past.
Recently diagnosed individuals with a history of stroke would
be expected to be at a higher risk for recurrence. We do not,
however, consider this exclusion to substantially have affected the results for the reasons that follow. The actual
prevalence of stroke in newly diagnosed diabetes is low,
considering data from the DIADEM and DICE studies.7,8
Even if 2% to 5% of subjects in our cohort had had a previous
stroke and were at a higher risk for recurrence, they would be
unlikely to substantially have affected the aggregate risk
estimates for the entire cohort. Furthermore, persons with a
past occurrence of stroke were not excluded from the general
population comparator either, so the comparison between the
2 groups should still be valid. Along the same lines, although
only the first stroke during the period of surveillance was
included for our diabetes cohort, individuals in the general
population also could have contributed recurrent stroke
events. This difference in case ascertainment would serve to
bias our results to the null, increasing the stroke rate in the
reference population group.
Figure 3. Kaplan–Meier survival curve for a first stroke hospitalization in the cohort of persons with newly treated type 2 diabetes mellitus. Subjects remaining in the cohort at specified time
points are as follows: at 2 years, 11 163; at 4 years, 8350; at 6
years, 4464; and at 8 years, 1228.
Third, we did not have access to important risk factor data,
such as glycosylated hemoglobin, blood pressure, cholesterol
levels, or body mass index in the diabetes cohort or the
general population. We would expect persons with type 2
diabetes to have a higher prevalence of obesity, hypertension,
and hypertriglyceridemia. Therefore, if other risk factor data
had been available and controlled for, it is possible that the
relative risk for stroke from diabetes alone might diminish.
However, the diabetes cohort would still be at a high risk for
stroke, regardless of whether the risk came from diabetes per
se or from the risk factors that cluster with diabetes. Last, we
drew our sample from 1 Canadian province that provides
universal healthcare (and comprehensive drug benefits) coverage to its population, and we may not be able to generalize
our results to other nations.
In summary, this study addressed a gap in the literature and
found that the risk of stroke in newly treated persons with
type 2 diabetes is 9.1% within the first 5 years. This stroke
rate is double that of the general population. An understanding of the high level of short-term risk for stroke, a devastating and disabling condition, will help to dispel the notion that
the macrovascular consequences of diabetes occur only in the
long term and hopefully will improve the motivation of both
patients and providers to aggressively control cardiovascular
risk factors soon after diagnosis.
Sources of Funding
The research project was supported by an Alliance for Canadian
Health Outcomes Research in Diabetes NET grant; the Canadian
Diabetes Association; the Kidney Foundation of Canada; the Canadian Institutes for Health Research (CIHR) Institute of Nutrition,
Metabolism, and Diabetes; the Heart and Stroke Foundation of
Canada; the CIHR Institute of Circulatory and Respiratory Health;
and the Heart and Stroke Foundation of Alberta, Northwest Territories, and Nunavut. Drs Majumdar and Simpson hold new investigator
awards from the CIHR. Dr Majumdar is also a Population Health
Investigator with the Alberta Heritage Foundation for Medical
Research. Dr Johnson is a Health Scholar with the Alberta Heritage
Foundation for Medical Research and holds a Canada Research
Chair in Diabetes Health Outcomes.
Disclosures
None.
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Short-Term Risk for Stroke Is Doubled in Persons With Newly Treated Type 2 Diabetes
Compared With Persons Without Diabetes. A Population-Based Cohort Study
Thomas Jeerakathil, Jeffrey A. Johnson, Scot H. Simpson and Sumit R. Majumdar
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Stroke. published online May 3, 2007;
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