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Mortality and Cardiovascular Risk of Sulfonylureas in South Asian, Chinese, and Other Patients Canadians with Diabetes
Running Head: Mortality Risk of Sulfonylureas in Patients with Diabetes
Authors: C Ke MD (1), S Morgan PhD (2), K Smolina PhD (2), D Gasevic MD, PhD (3), H Qian MSc (4), N Khan MD MSc (4, 5)
(1) Department of Medicine, University of Toronto, Toronto, Ontario, Canada(2) School of Population and Public Health, University of British Columbia, Vancouver,
British Columbia, Canada(3) Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK(4) Center for Health Evaluation and Outcomes Sciences, University of British Columbia,
Vancouver, British Columbia, Canada(5) Department of Medicine, University of British Columbia, Vancouver, British Columbia,
Canada
Word Count: 2325 words
Funding and Role of the Sponsor: This study was funded by the Canadian Institutes of Health Research (CIHR). The study sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. NAK is funded by a Michael Smith Foundation for Health Research Career Scientist award. This study was funded by the Canadian Institutes for Health Research.
Conflict of Interest: There are no potential conflicts of interest involving the work under consideration for publication (during the time involving the work, from initial conception and planning to present), no relevant financial activities outside the submitted work (over the 3 years prior to submission), and no other relationships or activities that readers could perceive to have influenced, or that give the appearance of potentially influencing what is written in the submitted work (based on all relationships that were present during the 3 years prior to submission) for any of the co-authors.
Novelty Statement: Sulfonylureas are used heavily in Asian populations, but there are no existing studies on
long-term mortality risk in South Asian and Chinese patients We observed a concerning signal for increased mortality and cardiovascular risk in all
patients, with across all ethnicities including significantly increased mortality risk in South Asian and Chinese patients
This paper highlights the potential dangers of sulfonylureas, and results should be confirmed in other studies including patients of Asian descent
1
Abstract
Aim: Sulfonylureas have been inconsistently associated with increased cardiovascular mortality in patients with type 2 diabetes mellitus (DM2). Globally, sulfonylureas are used heavily in Asian populations. However, there are no existing studies on long-term mortality risk of sulfonylureas in South Asian and Chinese populations. Our objective was to determine whether sulfonylureas are associated with increased mortality or cardiovascular disease in a population cohort of South Asian, Chinese, and other Canadian patients with incident diabetes.
Methods: We studied a population-based cohort of adults aged ≥35 years with diabetes diagnosed between April 2004 and March 2014 using administrative health databases from British Columbia, Canada. The pPrimary outcome was time to death from any cause or major cardiovascular event (MACE) with sulfonylurea treatment within each ethnic groupity. Propensity score modelling was applied using inverse probability of treatment weights. Results were stratified by agent and adjusted for age, sex, comorbidities, income, and other medications.
Results: There were 208 870 patients (13 755 South Asian, 22 871 Chinese, 172 244 other Canadians) included. Mortality and MACE was were significantly increased among other Canadian patients prescribed sulfonylureas (, with adjusted HR= 2.04, (95% confidence interval: 1.90-2.192;) and HR=1.9, 1.7-2.2). Among Chinese and South Asian patients prescribed sulfonylureas, mortality was also high with (HR= of 2.64, (2.02-3.475;) and and HR=2.39 4, (1.71-3.45) respectively) and MACE (HR=2.3, 1.4-4.0; and HR=2.0, 1.2-3.2 respectively) were elevated.
Conclusions: Considering the widespread use of sulfonylureas, there is a concerning significant signal for increased mortality in all patients. In particular, significantly increased mortality and MACE were risk was observed in South Asian and Chinese patients. These results should be confirmed in other studies and patients of Asian descent should be included in diabetes clinical trials.
2
Introduction
Sulfonylureas have been promoted by international guidelines as a glycemic control medication
in patients with type 2 diabetes (DM2). However, the safety of sulfonylureas has been called into
question for decades since the University Group Diabetes Program study reported an increased
mortality risk with tolbutamide in 1970.[1] Since then, numerous observational studies and
randomized control trials reported conflicting findings of increased cardiovascular and all-cause
mortality.[2–5]
Specifically, Forst et al.[5] performed a meta-analysis of observational cohort studies evaluating
all-cause and cardiovascular mortality among DM2 patients treated with sulfonylureas versus
non-sulfonylurea diabetes medications. They reported that odds ratios for all-cause and
cardiovascular mortality were increased, but findings were limited by the lack of randomized
control trial (RCT) data to control for confounding by indication. A meta-analysis of RCTs
comparing sulfonylureas to non-sulfonylurea treatment showed that sulfonylureas were
associated with significantly increased odds ratio for all-cause mortality but not for major
cardiovascular events (MACE).[3] A repeat meta-analysis of RCTs by Du et al.[4] excluding
first-generation sulfonylureas found that MACE, cardiovascular mortality, and all-cause
mortality were not significantly increased. A meta-analysis combining RCT and observational
studies of sulfonylureas found an increased relative risk of cardiovascular mortality and MACE
among patients treated with sulfonylureas compared to non-sulfonylurea treatment or metformin
treatment.[2] This increased risk was not demonstrated after excluding observational studies.
3
These mixed findings, while altogether suggestive, are limited by the inherent heterogeneity of
comparing studies in different patient populations.
Furthermore, most of the studies While most studies evaluating sulfonylureas were conducted in
primarily western Caucasian populations, with very limited , evidence specifically in Asian
populations is limited. One study of Chinese patients reported a higher hazard ratio of major
cardiovascular events (1.8, 1.1-3.3) when comparing those treated with glipizide to those treated
with metformin.[6] However, patients were only followed for 3 years and a mortality difference
was not detected at this duration. The ADOPT trial, one of the largest RCTs reporting no
mortality difference with a sulfonylurea, only included 2.4% patients of Asian ethnicity.[7] The
ADVANCE trial included a subset of 37% Asian patients, and reported that intensive glycemic
control using gliclazide did not increase mortality over 5 years in a subset of 37% Asian patients.
[8][7] However, this trial may not be representative of the general diabetes population, as it only
included patients with established macrovascular or microvascular disease or an additional
vascular disease risk factor. The ADVANCE trial also did not distinguish South Asian versus
Chinese patients, which is critical considering that genes related to sulfonylurea clearance occur
at differing frequencies depending on ethnicity.[9] Moreover, the experience with gliclazide may
differ from that of earlier sulfonylureas, which are still widely used in Asian countries globally.
[10]One study of Chinese patients reported a higher hazard ratio of major cardiovascular events
(1.8, 1.1-3.3) with glipizide compared to metformin.[6] However, patients were only followed
for 3 years and a mortality difference was not detected. The ADVANCE trial reported that
intensive glycemic control using gliclazide did not increase mortality over 5 years in a subset of
37% Asian patients.[7]
4
Sulfonylureas are used routinely among Asian patients both in Canada[11][8] and worldwide and
worldwide. There remains considerable uncertainty regarding long-term safety in Chinese and
South Asian patientsAsian populations, and it is unlikely that further large RCTs specifically
investigating these populations will be conducted. This gap is especially concerning in light of
the fact that sulfonylureas are still hugely popular used heavily use in Asia given their cheap cost
(65% of Japanese DM2 patients not on insulin,[12][9] 48% of oral hypoglycemic prescriptions in
Taiwan[13][10]). We conducted a population-based cohort study to determine whether
sulfonylureas are associated with increased mortality and MACE (acute myocardial infarction,
congestive heart failure, or stroke) in a cohort of South Asian, Chinese, and other Canadian
patients with newly-diagnosed diabetes.
Methods
Study Population
We analyzed adults aged ≥35 years living in British Columbia, Canada with diabetes diagnosed
during the period of April 1, 2004 to March 31, 2013. We defined diabetes diagnosis using a
validated algorithm (92.3% sensitivity and 96.9% specificity[14][11]) consisting of an
International Classification of Diseases (ICD) 9 or 10 code for diabetes for at least 1 hospital
discharge abstract or 2 physician claims within 2 years (ICD-9-CM: 250.x; ICD-10: E109, E119,
E139, E149, E101, E111, E131, E141, E105, E115, E135, and E145). We set a washout period
5
of minimum 3 years to identify incident cases of diabetes. Index date was defined as the first
encounter with a documented diabetes diagnosis.
Patients were categorized by income quintile and Charlson comorbidities. Income was estimated
based on Canadian household-specific and area-based datacensus data by assigning median
income derived from postal code.[12] In our patient population, up to two thirds of patients who
are prescribed sulfonylurea by 5 years after diagnosis were initially started within the first year.
Therefore, Wwithin each ethnicity, we classified patients as treated with a sulfonylurea
(gliclazide, glyburide, glipizide, glimepiride) if they received a prescription within 1 year after
diagnosis. We excluded patients who died within 1 month of prescription.
Data Sources
We analyzed de-identified datasets for the province of British Columbia, Canada (total
population 4.6 million, including 210 400 South Asian, 373 800 Chinese) from Population Data
BC.[15][13] Use of this information was approved by data stewards and the University of British
Columbia Behavioural Research Ethics Board. All inferences, opinions, and conclusions drawn
in this report are those of the authors, and do not reflect the opinions or policies of Population
Data BC. British Columbia has a universal health insurance program and a universal drug benefit
plan, which sets deductibles based on household income. Therefore, our data included all
residents except for those under federal jurisdiction for drug coverage (i.e., military, veterans,
inmates of federal penitentiaries, and status Indians living on reserves).
6
We extracted physician claims and ICD codes for all inpatient and outpatient encounters. We
obtained medication data from a provincial database (PharmaNet) which contains dates, names,
and dosages of all dispensed prescriptions from community pharmacies (validated accuracy of an
analogous database >99%).[11][8] Mortality data were obtained from a provincial vital statistics
database.
Ethnicity
Ethnicity is not recorded in Canadian health databases; therefore, we used surname analysis to
identify patients of South Asian (from Pakistan, India, or Bangladesh) and Chinese (from China,
Taiwan, or Hong Kong) origin. This These algorithms was were previously validated for
research using administrative health databases with 63-96% positive predictive value in South
Asians, and 81-92% positive predictive value among Chinese.[16–19][14] In British Columbia,
Tthe remaining population is 93.2% Caucasian, with comparatively small numbers from other
populations including Black, Hispanic, and Aboriginal.[20][15] and tThis group was thus
labelled as “other Canadians.”
MortalityOutcomes
Patients were followed for up to 4 years for total mortality and MACE. A MACE event was
classified as any hospitalization for acute myocardial infarction, congestive heart failure, or
stroke. We computed mortality risk of mortality and MACE for treated versus untreated patients
within each ethnicity. Results were further stratified by sulfonylurea agent.
7
Statistical Analysis
Comparisons of baseline characteristics for each ethnic group were made using the χ2 test for
categorical variables and analysis of variance for continuous variables.
We constructed Cox proportional hazards models comparing sulfonylurea treatment versus
untreated within each ethnic group using propensity score modelling with the inverse probability
of treatment weights method. Weight calculated as a propensity score determined by a
multivariable logistic regression model with sulfonylurea prescription as a binary outcome
variable and the following covariates as independent variables: age, sex, Charlson comorbidities,
income, and other medications (Table 1) prescribed within a month before or after diagnosis
(Supplementary Table 4). We also added an interaction term to this model to assess whether
ethnicity modified the relationship between sulfonylurea exposure and mortality. Weighting was
calculated as the inverse probability of receiving treatment and stabilized by multiplying
marginal probability of the actual treatment received.[21][16] Although adherence to prescribed
medications varies by ethnicity,[11] Ppower was insufficient to evaluate differences in mortality
within adherence levels for sulfonylureas. Patients were censored after 4 years or at death,
whichever came first.
All p values are 2-tailed, with p<0.05 considered significant. We used SAS version 9.2 (SAS
Institute Inc.).
8
Results
A total of 208 870 patients (13 755 South Asian, 22 871 Chinese, 172 244 other Canadians) were
included (Table 1). South Asians were diagnosed at a younger age, and there was a higher
proportion of other Canadian patients aged >65 years. More South Asian and Chinese patients
were in the lowest 2 income quintiles. Comorbidities were generally uncommon except for
hypertension. Other Canadian patients were more likely to be prescribed metformin at baseline,
with Chinese patients being least likely. Within one year of diabetes diagnosis, sulfonylureas
were prescribed more commonly in South Asian patients (7.5%) and other Canadian patients
(7.1%) compared to Chinese patients (5.0%). Patients treated with sulfonylureas were more
likely to be male (61.4% versus 34.0%) and prescribed metformin (64.5% versus 19.8%)
compared to those not treated with sulfonylureas.
During the follow-up period (median 3 years), 6.5% of patients died. This observed increase in
deaths was approximately 13.0 deaths per 1000 patient-years for Chinese patients, 10.6 deaths
for South Asian patients, and 14.2 deaths for other Canadian patients. Mortality was significantly
increased among other Canadian patients taking sulfonylureas (HR= 2.0, 1.9-2.2; Supplementary
Table 2). Among Chinese and South Asian treated patients, mortality was even higher, (HR=2.6,
2.0-3.5 and HR=2.4, 1.7-3.4 respectively). Interaction between sulfonylurea exposure and
ethnicity was significant (p=0.04). In terms of MACE, hazard ratios were similarly increased
across all ethnicities (South Asian HR=2.0, 1.2-3.2; Chinese HR=2.3, 1.4-4.0; other Canadian
HR=1.9, 1.7-2.2). After stratifying for type of sulfonylurea, hazard ratios for all-cause mortality
and MACE did not significantly change (Table 3).
9
Only glyburide and gliclazide were included in this stratification due to insufficient
prescriptions for other types of sulfonylureas.
Discussion
In Tthis large population-based analysis, we examined the risk of all-cause mortality and MACE
among patients prescribed associated with sulfonylurea prescriptions. Among patients of all
ethnicities, we found a significantly increased risk of mortality and MACErisk. These real-life
cohort study findings suggests a need for increased caution with this medication class.
Previous meta-analyses reported mixed findings regarding sulfonylurea safety.[2–5] Specifically,
meta-analyses of observational studies have described increased all-cause mortality (odds ratio
1.9, 1.5-2.5)[5] and increased cardiovascular mortality (relative risk 1.3, 1.2-1.3).[2] However,
meta-analyses of RCTs only have reported no association[2] or increased all-cause mortality
(odds ratio 1.2, 1.0-1.5)[3] only when first-generation sulfonylureas are included.[4]
Previous meta-analyses of numerous randomized control trials reported mixed findings regarding
sulfonylurea safety.[2–4] Some reported increased cardiovascular mortality (relative risk 1.3,
1.2-1.3)[2] and all-cause mortality (odds ratio 1.2, 1.0-1.5).[3] However, another found no
significant risk increase after excluding first-generation sulfonylureas.[4] While first-generation
sulfonylureas may be less safe, a meta-analysis of observational studies found a substantially
increased all-cause mortality odds ratio (1.9, 1.5-2.5).[5] Our analysis of modern-day
sulfonylureas prescribed in a real-life population confirms the these concerning
10
findingsincreased mortality associated with sulfonylurea prescription (other Canadians HR=2
2.0, 1.9-2.2) that was reported in meta-analyses of observational studies.. The risk we observed
for MACE (other Canadians HR=1.9, 1.7-2.2) was somewhat higher than the risk of composite
cardiovascular mortality combined with MACE (relative risk 1.1, 1.0-1.2) reported when
including both observational studies and RCTs.[2] However, the inherent heterogeneity of study
populations and designs included may limit the comparability of these results.
Among Chinese and South Asian patients, we observed disturbingly higherincreased risks of
mortality and MACE with sulfonylureas consistent with the rest of the study population. This
study is the first to our knowledge to demonstrate this adverse association in South Asians. For
Chinese patients, our results extend the findings of the SPREAD-DIMCAD study, that found that
glipizide caused significantly more major cardiovascular events in high-risk Chinese DM2
patients but did not detect any mortality difference.[6][6] Our results contrast with those of the
ADVANCE study, that reported no increased harm with gliclazide.[8][7] We found no
significant difference with gliclazide compared to glyburide across all ethnicities. This difference
may be related to differences in sulfonylurea use in a controlled study population compared to
use in a real-world setting.intra-class variability in associated mortality and cardiovascular
events.[4] Further research is required to clarify this hypothesis.
The explanations underlying these striking findings are not completely clear. It has been
proposed that sulfonylureas cause not only glucose-independent hypoglycemia, but also
cardiovascular side effects due to decreased myocardial ischemic preconditioning.[2] This would
be consistent with the observation that mortality risk was elevated in the same direction across
11
all ethnicities. We did find that ethnicity is an effect modifier (p=0.04), although mortality risk
and MACE were increased across all groups. Accordingly, There may also be genetic
polymorphisms causing differing responses by ethnicity may be playing a more minor role. For
example, cClearance of sulfonylureas such as glyburide, glimepiride, and glipizide is decreased
in patients carrying the CYP2C9*3 allele, resulting in more frequent severe hypoglycemia
among slow metabolizers.[22][17] Malaysian Indians were reported to have increased frequency
of this genotype, but at similar levels to other populations.[9][18] Han Chinese have decreased
frequency of this genotype, suggesting that there are likely other genes involved.[23][19]
Globally, sulfonylureas are still among the most popular diabetes medications given their cost,
especially in Asia.[13][10] The concerning important findings of this study suggest increased
caution in all patients, including those of South Asian and Chinese ethnicity. Considering the
decreasing costs and expanding armamentarium of diabetes medications, it may be more
judicious to preferentially utilize newer sulfonylureas or alternative agents where feasible.
Our population-based analysis examined the effect of sulfonylureas on mortality in a real-world
setting, controlling for confounding using propensity score techniques. As with all observational
studies, there are some limitations to note. While we adjusted for use of other diabetes
medications and comorbidities shown to predict mortality in diabetes patients, it is possible that
selection bias influenced our results. Ssulfonylureas may have been prescribed as second-line
agents within the first year of diagnosis indicating more severe diabetes with higher risk for
complications, we adjusted for use of other diabetes medications and comorbidities shown to
predict mortality in diabetes patients. We were unable to control for rresidual confounding from
12
unmeasured variables not captured in this study, including such as smoking status, body mass
index, hypoglycemia frequency and glycemic control. In terms of drug exposure, iWe were also
unable to examine adherence effects due to insufficient powert is possible that patients were
misclassified due to switching onto or off of sulfonylurea therapy after 1 year, thus reducing
generalizability to patients taking sulfonylureas later in life. We were also unable to control for
differing levels of drug adherence due to lack of power. However, decreased adherence or
switching off sulfonylureas would tend to conservatively bias the results in the null direction.
Further research is required to explore this effect.The surname algorithms used to identify
ethnicity could have introduced misclassification due to mixed marriages, but this possibility is
less likely given that 90.5-93.2% of South Asian and Chinese marriages in Canada are within the
same ethnic background.[24]
Conclusion
Despite the widespread use of sulfonylureas as promoted by global guidelines, there is a
concerning signal for increased mortality in all patients. In particular, a drastically significantly
increased mortality risk was observed in South Asian and Chinese patients. These results require
confirmation in other studies and taken in context with results in previous meta-analyses, provide
further evidence for the cautious use of sulfonylureas among all patients with DM2.
13
Figures and Tables
Table 1 Baseline characteristics among diabetes patients aged 35 years and older in British Columbia, stratified by ethnicity and sulfonylurea treatment
Ethnicity Sulfonylurea Treatment
Characteristics South Asian(n=13 755)
Chinese(n=22 871)
Other Canadians(n=172 244)
p-value Not Treated(n=192
259)
Treated(n=13 611)
p-value
Age, mean age (years) ±SD or %
All patients 56.4 ±12.6
59.2 ±12.7
61.5 ±12.8
<0.0001 61.0 ±12.8
59.2 ±13.4
<0.0001
35-49 years 33.2 24.7 18.8 <0.0001 20.0 26.0 <0.000150-64 years 39.8 43.1 42.0 42.0 41.565-79 years 23.2 25.3 29.5 29.0 23.7≥80 years 3.879 6.8 9.7 9.0 8.8
Women (%) 45.0 48.4 45.1 <0.0001 45.9 38.5 <0.0001Income Quintile (%)
1st quintile (low) 25.6 27.4 21.2 <0.0001 21.9 25.8 <0.00012nd quintile 32.2 23.4 20.7 21.7 22.63rd quintile 20.4 20.2 20.0 20.1 20.04th quintile 12.3 14.4 19.3 18.4 16.85th quintile (high) 8.8 13.4 17.5 16.7 13.5Unknown 0.7 1.0 1.2 1.2 1.4
Charlson Comorbidities (%)Hypertension 42.0 44.0 47.9 <0.0001 47.8 36.6 <0.0001Myocardial infarction 2.2 1.0 2.6 <0.0001 2.4 2.9 0.0005
Congestive heart failure 3.0 2.1 5.3 <0.0001 4.7 5.7 <0.0001
Peripheral vascular disease 0.6 1.3 2.0 <0.0001 1.8 1.6 0.08
Cancer 2.8 3.8 6.3 <0.0001 5.8 5.8 0.9Cerebrovascular disease 1.8 2.0 3.2 <0.0001 3.0 3.1 0.5
Chronic pulmonary disease 11.2 6.4 11.4 <0.0001 10.8 10.5 0.2
Renal disease 2.2 2.3 3.1 <0.0001 2.9 3.9 <0.0001Medications at baseline* n (%)
Metformin 21.3 15.4 23.8 0.0001 19.8 64.5 <0.0001Sulfonylurea 3.8 2.6 3.5 <0.0001 0.07 51.9 <0.0001Insulin 0.6 0.7 1.7 <0.0001 1.4 3.4 <0.0001
14
Statin 24.2 20.8 26.9 <0.0001 25.8 30.0 <0.0001ACEi 15.7 11.0 22.8 <0.0001 20.5 28.1 <0.0001ARB 7.2 10.0 8.7 <0.0001 8.8 8.0 0.002CCB 8.1 9.1 8.5 0.0008 8.4 9.8 <0.0001Diuretic 11.3 12.4 18.3 <0.0001 17.3 15.6 <0.0001β-blocker 9.5 8.4 13.3 <0.0001 12.4 13.9
*within 1 month before or after diabetes diagnosis
Abbreviations: SD = standard deviation, ACEi = angiotensin converting enzyme inhibitor, ARB = angiotensin receptor blocker, CCB = dihydropyridine calcium channel blocker
Supplementary Table 2 Association of sulfonylurea medications and outcomes total mortality according to ethnicity
Adjusted HR* (95% CI)South Asian
p-value Chinese p-value Other Canadians
p-value
Treated with SulfonylureasAll-cause mortality
2.39 (1.71-3.45)
<0.0001 2.64(2.02-3.47)
<0.0001 2.04(1.90-2.19)
<0.0001
Major cardiovascular events†
1.99(1.22-3.24)
0.006 2.32(1.35-4.00)
0.002 1.93(1.66-2.24)
<0.0001
* Cox proportional hazards models were weighted using a propensity score model by the inverse probability of treatment weights method adjusted for age, sex, SES, Charlson comorbidities, and use of other medications (insulin, ACEi, ARB, beta-blockers, CCB, diuretics, and statins) at baseline, defined as a prescription within 1 month before or after diagnosis.↑ Major cardiovascular events included all acute myocardial infarction, congestive heart failure, and stroke eventsAbbreviations: HR = hazard ratio, ACEi = angiotensin converting enzyme inhibitor, ARB = angiotensin receptor blocker, CCB = dihydropyridine calcium channel blocker
Table 3 Association of sulfonylurea medications and outcomes according to drug and ethnicity Adjusted HR* (95% CI)
South Asian
p-value Chinese p-value Other Canadians
p-value
Glyburide
All-cause mortality
2.36(1.59-3.52)
<0.0001 2.30(1.60-3.31)
<0.0001 1.97(1.81-2.16)
<0.0001
Major cardiovascular events†
2.09(1.20-3.64)
0.009 2.55(1.31-4.96)
0.006 1.87(1.55-2.24)
<0.0001
Gliclazide
All-cause mortality
2.30(1.38-3.81)
0.001 3.28(2.30-4.66)
<0.0001 2.02(1.82-2.24)
<0.0001
15
Major cardiovascular events†
1.63(0.72-3.67)
0.2 2.53(1.16-5.48)
0.02 1.86(1.50-2.29)
<0.0001
* Cox proportional hazards models were weighted using a propensity score model by the inverse probability of treatment weights method adjusted for age, sex, SES, Charlson comorbidities, and use of other medications (insulin, ACEi, ARB, beta-blockers, CCB, diuretics, and statins) at baseline, defined as a prescription within 1 month before or after diagnosis.↑ Major cardiovascular events included all acute myocardial infarction, congestive heart failure, and stroke eventsAbbreviations: HR = hazard ratio
Supplementary Table 43 Covariates used in propensity score model
Effect Point Estimate 95% Wald Confidence Limits
Age 1.00 1.00 1.00Female vs. male sex 0.80 0.71 0.911st vs. 5th income quintile 1.42 1.14 1.772nd vs. 5th income quintile 1.25 1.00 1.583rd vs. 5th income quintile 1.46 1.16 1.844th vs. 5th income quintile 1.28 1.00 1.65Charlson comorbidity index 0 vs. 23 0.69 0.52 0.91Charlson comorbidity index 1 vs. 23 0.61 0.45 0.83Metformin 0.14 0.12 0.16Insulin 0.29 0.18 0.47Statin 0.98 0.85 1.14ACEi 0.71 0.60 0.85ARB 1.06 0.85 1.32CCB 0.87 0.71 1.06Diuretic 1.24 1.02 1.52β-blocker 0.82 0.66 1.00
Abbreviations: SD = standard deviation, ACEi = angiotensin converting enzyme inhibitor, ARB = angiotensin receptor blocker, CCB = dihydropyridine calcium channel blocker
16
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PharmaNet; Vital Statistics Deaths [Internet]. Population Data BC; BC Ministry of Health; 2012 2014. Available from: http://www.popdata.bc.ca/data
14. Shah BR, Chiu M, Amin S, Ramani M, Sadry S, Tu JV. Surname lists to identify South Asian and Chinese ethnicity from secondary data in Ontario, Canada: a validation study. BMC Med Res Methodol. 2010 May 15;10:42.
15. Government of Canada SC. Tables by subject: Ethnic diversity and immigration [Internet]. 2013 [cited 2013 Feb 27]. Available from: http://www.statcan.gc.ca/tables-tableaux/sum-som/l01/ind01/l2_30000-eng.htm
16. Austin PC. The use of propensity score methods with survival or time-to-event outcomes: reporting measures of effect similar to those used in randomized experiments. Stat Med. 2014 Mar 30;33(7):1242–58.
17. Holstein A, Plaschke A, Ptak M, Egberts E-H, El-Din J, Brockmoller J, et al. Association between CYP2C9 slow metabolizer genotypes and severe hypoglycaemia on medication with sulphonylurea hypoglycaemic agents. Br J Clin Pharmacol. 2005 Jul;60(1):103–6.
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