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

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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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