Journal of Diabetes and Its Complications 29 (2015) 196–202

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Comparative cardiovascular safety of insulin secretagogues following hospitalization for ischemic heart disease among type 2 diabetes patients: a cohort study Yuhao Huang a, Ahmed S. Abdelmoneim b, Peter Light d, Weiyu Qiu c, Scot H. Simpson b,⁎ a b c d

Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, 8440 122 St. NW, Edmonton, Alberta, Canada, T6G 2R7 Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, 11405 87 Ave. NW, St. Edmonton, Alberta, Canada, T6G 1C9 School of Public Health, University of Alberta, 11405–87 Ave, Edmonton, Alberta, Canada, T6G 1C9 Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, 8440 122 St. NW, Edmonton, Alberta, Canada, T6G 2R7

a r t i c l e

i n f o

Article history: Received 15 September 2014 received in revised form 20 November 2014 accepted 21 November 2014 Available online 2 December 2014 Keywords: Ischemic heart disease Insulin secretagogue Retrospective cohort study Type 2 diabetes Atrial fibrillation

a b s t r a c t Aim: To evaluate the association between insulin secretagogues and adverse cardiovascular sequelae in type 2 diabetes patients hospitalized for ischemic heart disease (IHD). Methods: Administrative health records from Alberta, Canada between 1998 and 2010 were used to identify 2,254 gliclazide, 3,289 glyburide and 740 repaglinide users prior to an IHD-related hospitalization. Multivariable Cox regression models were used to compare the 30-day risk of a composite outcome of allcause mortality or new onset of atrial fibrillation, stroke, heart failure or myocardial infarction according to insulin secretagogue use. Results: Mean (SD) age was 76.1 (6.9) years, and 60.7% were men. The composite outcome occurred in 322 (30.2%) gliclazide users, 455 (28.1%) glyburide users and 81 (23.4%) repaglinide users within 30 days of IHD hospitalization. There were no differences in risk for glyburide use (adjusted hazard ratio [aHR] 0.91; 95% confidence interval [CI] 0.78–1.05) or repaglinide use (aHR 0.80; 95% CI 0.63–1.03) compared to gliclazide. Similar results were observed in analyses for each element of the composite outcome. Conclusions: In older patients with type 2 diabetes hospitalized for IHD, prior use of gliclazide, glyburide, or repaglinide appears to be associated with a similar risk of adverse cardiovascular sequelae. © 2015 Elsevier Inc. All rights reserved.

1. Introduction The cardiovascular safety associated with insulin secretagogue (IS) use in patients with type 2 diabetes remains a contentious issue (Forst et al., 2013; Monami, Nardini, & Mannucci, 2014; Phung, Sobieraj, Engel, & Rajpathak, 2013). Two prevailing theories have been proposed to explain why IS use appears to be associated with an increased risk of adverse cardiovascular events. First, hypoglycemia, a common adverse reaction associated with these drugs, especially glyburide (Gangji, Cukierman, Gerstein, Goldsmith, & Clase, 2007), can prolong the QT interval and has been associated with cardiac ischemia (Desouza, Salazar, Cheong, Murgo, & Fonseca, 2003; Landstedt-Hallin, Englund,

Conflict of interest: There are no potential conflicts of interest related to this article, and the authors have nothing to disclose. ⁎ Corresponding author at: Faculty of Pharmacy & Pharmaceutical Sciences, 3–171 Edmonton Clinic Health Academy, University of Alberta, 11405–87 Ave., Edmonton, Alberta, T6G 1C9. Tel.: +1 780 492 7538; fax: +1 780 492 1217. E-mail addresses: [email protected] (Y. Huang), [email protected] (A.S. Abdelmoneim), [email protected] (P. Light), [email protected] (W. Qiu), [email protected] (S.H. Simpson). http://dx.doi.org/10.1016/j.jdiacomp.2014.11.012 1056-8727/© 2015 Elsevier Inc. All rights reserved.

Adamson, & Lins, 1999). The second is an extension of the mechanism of action for IS. These oral antidiabetic drugs promote insulin secretion by binding to sulfonylurea receptors (SUR) and inhibiting ATP-sensitive potassium (KATP) channels in pancreatic beta cells (Ashcroft & Rorsman, 1989; Gromada, Dissing, Kofod, & Frøkjaer-Jensen, 1995). However, there may be important differences among IS based on SUR binding characteristics. Endocrine cells primarily express the SUR1 isoform while cardiac myocytes and smooth muscle cells primarily express SUR2 (Lang & Light, 2010). Some IS, like glyburide and the non-sulfonylurea IS repaglinide, will bind to both SUR1 and SUR2 isoforms when given at usual therapeutic doses and therefore also inhibit KATP channels located in the myocardium and vascular smooth muscle cells (Abdelmoneim et al., 2012). Animal models have shown that cardiac KATP channel opening is protective during ischemia–reperfusion injury and that KATP channel activity is essential for ischemic conditioning, an endogenous protective mechanism that promotes salvage of myocardial tissue during ischemia–reperfusion injury (Kristiansen et al., 2011; Tang et al., 2006). The extra-pancreatic cardiovascular effects of glyburide and repaglinide may potentially increase the risk of adverse cardiovascular events. In contrast, gliclazide appears to be more selective for SUR1, which may confer a better cardiovascular prognosis during acute

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ischemic events (Abdelmoneim et al., 2012; Kristiansen et al., 2011). Indeed, we have shown previously that gliclazide use is associated with a lower risk of acute coronary syndrome-related morbidity and mortality compared to glyburide use (Abdelmoneim et al., 2014). In contrast to the hypothesized adverse cardiovascular effects affiliated with IS-mediated interference of ischemic conditioning, there may be beneficial effects in the atria (Baczkó, Husti, Lang, Leprán, & Light, 2011; Riveline, Danchin, Ledru, Varroud-Vial, & Charpentier, 2003). Inhibition of KATP channels in the atria increases action potential duration during ischemia–reperfusion injury and can reduce the occurrence of atrial fibrillation (Kantor, Coetzee, Carmeliet, Dennis, & Opie, 1990; Kim et al., 2012). In this regard, previous experimental and clinical studies have demonstrated that prolonged closure of cardiac KATP channels by glyburide decreases the effects of pro-arrhythmic substrates and reduces the risk of re-entry arrhythmias, such as atrial fibrillation (Baczkó et al., 2011; Furukawa, Kimura, Furukawa, Bassett, & Myerburg, 1991; Kim et al., 2012). As ischemic events in patients with diabetes can increase the likelihood of myocardial conduction anomalies (Ghuran & Camm, 2001; Pedersen, Bagger, Køber, & Torp-pedersen, 1999), it is important to determine the effects of IS on atrial fibrillation. Given the mixture of possible adverse and beneficial cardiovascular effects and potential differences in tissue-specific binding amongst the IS, we hypothesized that the risk of adverse cardiovascular sequelae, including mortality or new onset of atrial fibrillation, stroke, heart failure or myocardial infarction, would be different amongst patients using gliclazide, glyburide, or repaglinide prior to hospitalization for ischemic heart disease (IHD). 2. Methods 2.1. Subjects & setting We conducted a population-based retrospective cohort study of all Alberta residents aged 65 years or older with one or more dispensations for an oral antidiabetic drug. The province of Alberta maintains administrative health records for this patient group while providing universal coverage for hospital care, physician services, and prescription drugs. These administrative health records are linkable through a unique anonymized number for each individual and have been used extensively in previous epidemiologic studies because of the high level of accuracy and completeness of data (Abdelmoneim et al., 2014; Gamble et al., 2011; Li, Evans, Faris, Dean, & Quan, 2008; Majumdar et al., 2013; So, Evans, & Quan, 2006). The University of Alberta Health Research Ethics Board approved the study protocol. We employed a two-stage process to construct the main study cohort. First, we identified all subjects who received at least one dispensation for an IS between January 1998 and December 2010 and with at least one year of continuous coverage following the first IS dispensation record. Second, we restricted our cohort to subjects with an ischemic heart disease (IHD) hospitalization following their first IS dispensation record. A hospitalization was considered attributable to IHD if the primary diagnostic field contained the International Classification of Diseases, 9th revision (ICD-9) codes 410, 411, 412, 413, or 414, ICD-10 codes I20, I21, I22, I23, I24, or I25, or the patient received a percutaneous coronary intervention (PCI) based on procedure codes IJ50, 1IJ57GQ, 1IJ54GQAZ, or 360. If a patient had multiple IHD hospitalizations during the observation period, we only considered the first IHD admission following their first IS dispensation record. The index date was defined as the admission date for the first IHD hospitalization following the first IS dispensation record. 2.2. Exposure assessment Exposure was determined based on dispensation records for an IS within 120 days before the index date. A 120-day exposure window was used because the provincial drug plan covers a 100-day supply for

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antidiabetic drugs, and we allowed for an average adherence rate of 80% (Abdelmoneim et al., 2014; Cramer, 2004). Five different IS were identified in the Alberta Blue Cross database during our study period: gliclazide, glyburide, repaglinide, tolbutamide, and chlorpropamide. We excluded patients with no IS dispensations as well as those with more than one type of IS dispensed within the 120-day exposure window. Subjects who received tolbutamide (n = 22) or chlorpropamide (n = 46) were also excluded due to low numbers (data available on request). 2.3. Outcome measures The primary outcome was a composite of all-cause mortality or new onset of atrial fibrillation, stroke, heart failure or myocardial infarction within 30 days following the index date. If a patient experienced more than one component of the composite outcome (for example, developed new onset of atrial fibrillation and died), we only counted the first event. Secondary outcomes included individual components of the composite outcome as well as cardiovascularrelated mortality. To identify a new onset of atrial fibrillation, stroke, heart failure or myocardial infarction, we excluded patients with a physician visit or hospitalization record for the specific outcome of interest within the previous 3 years of the index date. For all analyses, follow-up of patients who did not have the outcome of interest was censored 30 days after the index date, when the patient moved out-of-province, or the end of our study observation period (December 31st, 2010). All-cause mortality and cardiovascular-related mortality were identified using the Vital Statistics database and ICD-9 or ICD-10 codes for the underlying cause of death. Atrial fibrillation, stroke, heart failure, and myocardial infarction were identified using ICD codes of the respective outcome of interest from any diagnostic field recorded in the hospitalization or emergency room visit records (Appendix; Table 1). These codes have been used in other studies to identify the outcomes of interest and have high positive predictive values (atrial fibrillation – 89%; stroke – 81%; heart failure – 90%; and myocardial infarction – 94%) (Jensen et al., 2012; Lee et al., 2013; Quan et al., 2005, 2008; Varas-lorenzo et al., 2008). 2.4. Covariates All baseline characteristics were identified from administrative health records within the previous 3 years of the index date. In addition to sex, age, and index year, we identified dispensation information from Alberta Blue Cross for antihypertensive drugs, lipid lowering drugs, digoxin, antiplatelet drugs, oral anticoagulants, hormone replacement therapy, COX-2 inhibitors, anti-arrhythmia drugs, oral antidiabetic drugs and insulin. We used information from physician visits, emergency room visits and hospitalization records to identify a list of comorbid conditions (Elixhauser, Steiner, Harris, & Coffey, 1998), as well as hypoglycemia, cerebrovascular disease and hyperlipidemia. Comorbid conditions were collapsed into a single score representing the number of comorbidities (Abdelmoneim et al., 2014). To control for possible differences in management of patients using gliclazide, glyburide, or repaglinide, we identified physician service codes for guideline concordant procedures, which included retinopathy screening, lipid, blood glucose or renal function assessment Committee CDACPGE, as well as mammography and bone mineral densitometry screening. 2.5. Statistical analyses Patients were grouped according to use of gliclazide, glyburide, or repaglinide prior to the index date, and descriptive statistics were calculated for baseline characteristics. Categorical variables were compared by χ 2 tests, and continuous variables were compared using one-way ANOVA.

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Cox proportional hazards regression models were built to estimate the crude and adjusted hazard ratios (HR), as well as a 95% confidence interval (CI) for each outcome of interest, with gliclazide use serving as the reference group. Multivariable models were adjusted for age, sex, index year, type of IHD for index hospitalization, concomitant drug usage, comorbidity score and guideline concordant procedures. All first order interactions between IS exposure and each covariate were examined, with none achieving statistical significance (p N 0.05 for all). All analyses were conducted using Stata 12 (StataCorp LP, College Station, TX, USA).

2.6. Sensitivity analyses To explore the potential for exposure misclassification, we repeated our analyses by altering the exposure window to 30 days and 1 year prior to the index date. We also extended the follow-up period to 1 year to explore the long-term risk of the primary outcome. Since we did not have information on the duration of diabetes for each subject, we performed a sub-group analysis by restricting the study cohort to new IS users. New IS users were identified using a 1-year washout period prior to the first IS dispensation record. Further, to account for potential immeasurable-time bias (Suissa, 2008), we excluded all patients with any hospitalization during the 120-day exposure window. Finally, we repeated our primary composite outcome analysis using high-dimensional propensity-score matching between patients using gliclazide or glyburide (Schneeweiss et al., 2009). The score was constructed using data within 3 years of the index date, including the number and type of drug dispensations, diagnosis and procedure codes recorded during hospitalizations and emergency visits, physician claims, as well as patient demographics on the index date. Gliclazide users were matched one-to-one with glyburide users on a propensity score within 0.2 standard deviations (Dehejia & Wahba, 2002).

125,565

3. Results 3.1. Patient cohort Between January 1998 and December 2010, we identified 125,565 patients with dispensations for oral antidiabetic drugs (Fig. 1). Of the 69,902 (55.7%) patients who received an IS dispensation, 10,733 (15.4%) were subsequently hospitalized for an IHD event. We further excluded 3,404 (31.7%) patients because they either received more than one type of IS or did not receive any IS during the 120-day exposure window. The final cohort included 2,254 (35.9%) patients who received gliclazide, 3,289 (52.3%) who received glyburide and 740 (11.8%) who received repaglinide within 120 days before the index IHD hospitalization. Mean age was 76.1 (SD 6.9), 60.7% were men, and median number of comorbidities was 5.0 (IQR 4.0 to 7.0) (Table 1). With the exception of acarbose, baseline prevalence of hypertensive, lipid lowering, antiplatelet, anticoagulant, and other antidiabetic drug use differed amongst gliclazide, glyburide, and repaglinide users. Likewise, prevalence of co-morbid conditions varied across the three IS user groups.

3.2. Composite outcome Among the 6,283 patients included in this study, 3,252 had a hospitalization or physician visit record indicating pre-existing atrial fibrillation, stroke, heart failure or myocardial infarction within 3 years prior to the index date and were excluded from the primary composite outcome analysis. The primary composite outcome occurred in 322 (30.2%) of 1,066 gliclazide users, 455 (28.1%) of 1,619 glyburide users, and 81 (23.4%) of 346 repaglinide (Table 2). Compared to gliclazide users, risk of the primary composite outcome was similar for glyburide users (aHR 0.91; 95% CI 0.78–1.05) and repaglinide users (aHR 0.80; 95% CI 0.63–1.03).

Alberta Blue Cross beneficiaries who received ≥ 1 dispensation for an oral antidiabetic drug between 1 January 1998 and 31 December 2010

Exclusions (55,663) 605 Missing age or gender data 55,058 No IS dispensations

69,902

Patients received ≥ 1 dispensation for an IS Exclusions (59,169) 59,169 No hospitalizations for IHD following the first IS dispensation record

10,733

6,283

Patients with at least one hospitalization for IHD following the first IS dispensation record

Patients received ≥ 1 dispensation for gliclazide, glyburide or repaglinide within 120 days prior to the index hospitalization for IHD

IHD = Ischemic Heart Disease; IS = Insulin Secretagogue Fig. 1. Patient flow diagram.

Exclusions (4,450) 3,151 No IS dispensations during the 120-day exposure window 253

Received more than one type of IS during the 120-day exposure window

46

Received chlorpropamide only

22

Received tolbutamide only

916

Patients under the age of 65 years old on the index date

62

Patients without 1-year drug coverage on the index date

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Table 1 Baseline demographics.

Age, mean (SD), years Men Entry by year 1998–2001 2002–2005 2006–2010 Reasons for Index IHD hospitalization Angina Myocardial infarction Percutaneous coronary intervention other ischemic heart diseasesa Antidiabetic drugsb Metformin Thiazolidinediones Acarbose Insulin Other drugsb Antihypertensive drugs Lipid lowering drugs Digoxin Antiplatelet drugs Anticoagulant drugs Hormone replacement therapy COX-2 inhibitors Anti-arrhythmia drugs Comorbid conditionsb Congestive heart failure Cardiac arrhythmia Valvular disease Pulmonary circulation disorder Cerebrovascular disease Peripheral vascular disease Hypertension Hypercholesterolemia Liver disease Renal failure Depression Hypoglycemia ER visit Comorbidity score, median (IQR) Guideline concordant management

Gliclazide(n = 2,254)

Glyburide(n = 3,289)

Repaglinide(n = 740)

p-value

76.2 (7.1) 1,375 (61.0)

76.0 (6.8) 1,977 (60.1)

75.9 (6.7) 460 (62.2)

0.54 0.54 b0.01

664 (29.5) 761 (33.8) 829 (36.8)

1,589 (48.3) 1,087 (33.0) 613 (18.6)

50 (6.8) 241 (32.6) 449 (60.7)

634 768 215 637

(28.1) (34.1) (9.5) (28.3)

804 1,122 302 1,061

(24.5) (34.1) (9.2) (32.3)

202 (27.3) 256 (34.6) 86 (11.6) 196 (26.5)

1,615 436 116 238

(71.7) (19.3) (5.2) (10.6)

2,235 497 186 293

(68.0) (15.1) (5.7) (8.9)

577 (78.0) 226 (30.5) 32 (4.3) 143 (19.3)

b0.01 b0.01 0.31 b0.01

2,076 1,261 321 237 376 130 553 60

(92.1) (55.9) (14.2) (10.5) (16.7) (5.8) (24.5) (2.7)

2,922 1,466 471 219 440 172 731 108

(88.8) (44.6) (14.3) (6.7) (13.4) (5.2) (22.2) (3.3)

711 (96.1) 530 (71.6) 102 (13.8) 113 (15.3) 129 (17.4) 50 (6.8) 165 (22.3) 25 (3.4)

b0.01 b0.01 0.93 b0.01 b0.01 0.24 0.12 0.37

340 (46.0) 280 (37.8) 111 (15.0) 66 (8.9) 145 (19.6) 152 (20.5) 660 (89.2) 263 (35.5) 18 (2.4) 211 (28.5) 170 (23.0) 47 (6.4) 6.0 (4.0–9.0) 659 (89.1)

0.50 0.074 0.19 b0.01 0.44 b0.01 b0.01 b0.01 0.63 b0.01 b0.01 0.21 b0.01 0.017

b0.01

998 (44.3) 797 (35.4) 283 (12.6) 160 (7.1) 395 (17.5) 418 (18.5) 2,007 (89.0) 753 (33.4) 43 (1.9) 385 (17.1) 447 (19.8) 112 (5.0) 6.0 (4.0–8.0) 1,913 (84.9)

1,434 (43.6) 1,107 (33.7) 416 (12.7) 196 (6.0) 591 (18.0) 537 (16.3) 2,764 (84.0) 970 (29.5) 63 (1.9) 415 (12.6) 549 (16.7) 195 (5.9) 5.0 (3.0–7.0) 2,832 (86.1)

COX-2 = cyclooxygenase-2, ER = emergency room; IHD = ischemic heart disease, IQR = interquartile range. a Other acute and subacute forms of ischemic heart disease, other forms of chronic ischemic heart disease. b Baseline drugs and comorbid condition status were identified from dispensation records, physician visits, emergency room visits and hospitalizations up to 3 years prior to index date.

3.3. Mortality The 30-day incidence of all-cause mortality was 223 (9.9%) of 2,254 gliclazide users, 282 (8.6%) of 3,289 glyburide users, and 69 (9.3%) of 740 repaglinide users. After adjusting for confounding variables, there was no significant difference in risk for glyburide use (aHR 0.84; 95% CI 0.70–1.01) or repaglinide use (aHR 0.99; 95% CI 0.75–1.31) compared to gliclazide use (Table 2). We observed similar associations for risk of cardiovascular-related mortality amongst the three IS users (Table 2). 3.4. New onset atrial fibrillation A total of 958 patients had a history of atrial fibrillation prior to the index date and were therefore excluded from this analysis. The 30-day incidence of new onset atrial fibrillation was 204 (10.7%) of 1,908 gliclazide users, 276 (9.7%) of 2,836 glyburide users and 60 (9.8%) of 614 repaglinide users (Table 2). No significant differences were observed in the risk of developing new atrial fibrillation amongst the three IS users. 3.5. New onset stroke In 5,485 patients with no history of stroke in the 3-year period before the index date, a new stroke occurred in 53 (2.7%) of 1,985

gliclazide users, 73 (2.6%) of 2,867 glyburide users and 12 (1.9%) of 633 repaglinide users. There were no significant differences in the risk of stroke amongst the three IS users (Table 2).

3.6. New onset heart failure We excluded 2,342 patients who had a diagnosis of heart failure within 3 years prior to their index date. In the remaining 3,941 patients, new onset heart failure occurred in 188 (13.2%) of 1,422 gliclazide users, 262 (12.6%) of 2,083 glyburide users and 45 (10.3%) of 436 repaglinide users. After adjustment for covariates, the 30-day risk of new onset heart failure was similar amongst the three IS users (Table 2).

3.7. New onset myocardial infarction A total of 5,290 patients who did not have a history of myocardial infarction within 3 years before their index date were included. The 30-day incidence of new onset myocardial infarction was 73 (3.9%) of 1,890 gliclazide users, 126 (4.5%) of 2,786 glyburide users and 19 (3.1%) of 614 repaglinide users. After adjustment for covariates, the 30-day risk of new onset myocardial infarction was similar amongst the three IS users (Table 2).

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Table 2 Risk of adverse cardiovascular sequelae within 30 days after hospitalization for ischemic heart disease. N Composite outcomea Gliclazide 1,066 Glyburide 1,619 Repaglinide 346 All-cause mortality Gliclazide 2,254 Glyburide 3,289 Repaglinide 740 Cardiovascular mortality Gliclazide 2,254 Glyburide 3,289 Repaglinide 740 Atrial fibrillation Gliclazide 1,908 Glyburide 2,836 Repaglinide 614 Stroke Gliclazide 1,985 Glyburide 2,867 Repaglinide 633 Heart failure Gliclazide 1,422 Glyburide 2,083 Repaglinide 436 Myocardial infarction Gliclazide 1,890 Glyburide 2,786 Repaglinide 614

Patients with an event, n (%)

Unadjusted HR (95% CI)

Adjusted HR (95% CI)

322 (30.2) 455 (28.1) 81 (23.4)

1.00 0.92 (0.80–1.06) 0.75 (0.59–0.96)

1.00 0.91 (0.78–1.05) 0.80 (0.63–1.03)

223 (9.9) 282 (8.6) 69 (9.3)

1.00 0.86 (0.72–1.02) 0.94 (0.72–1.23)

1.00 0.84 (0.70–1.01) 0.99 (0.75–1.31)

167 (7.4) 238 (7.2) 57 (7.7)

1.00 0.97 (0.79–1.18) 1.03 (0.77–1.40)

1.00 0.92 (0.75–1.13) 1.14 (0.84–1.56)

204 (10.7) 276 (9.7) 60 (9.8)

1.00 0.90 (0.75–1.08) 0.91 (0.68–1.21)

1.00 0.98 (0.81–1.19) 0.90 (0.67–1.21)

53 (2.7) 73 (2.6) 12 (1.9)

1.00 0.95 (0.66–1.35) 0.70 (0.38–1.31)

1.00 0.92 (0.63–1.32) 0.80 (0.42–1.52)

188 (13.2) 262 (12.6) 45 (10.3)

1.00 0.95 (0.78–1.14) 0.77 (0.55–1.06)

1.00 0.98 (0.80–1.19) 0.78 (0.56–1.09)

73 (3.9) 126 (4.5) 19 (3.1)

1.00 1.16 (0.87–1.55) 0.79 (0.47–1.30)

1.00 1.07 (0.79–1.44) 0.87 (0.52–1.46)

HR = hazard ratio. a Composite outcome: all-cause mortality, or new onset of atrial fibrillation, stroke, heart failure, or myocardial infarction.

3.8. Sensitivity analyses Changing the exposure window to 30 days or 1 year, or extending the follow-up period to 1 year did not affect the magnitude, direction or statistical significance of our observed associations compared to our main results (Appendix; Table 2). Similarly, restricting our analyses to new IS users, excluding patients hospitalized during the 120-day exposure window, and conducting a matched analysis using high-dimensional propensity scores produced associations that were consistent with the main analyses. 4. Discussion We used administrative health data from Alberta, Canada between 1998 and 2010 to identify 6,283 patients who received an IS within 120 days of hospitalization for IHD. We found no significant differences in mortality or adverse cardiovascular sequelae amongst patients using gliclazide, glyburide, or repaglinide. Our findings are consistent with previous observational studies reporting similar risks amongst IS for adverse cardiovascular outcomes following a hospitalization for myocardial infarction (Arruda-Olson et al., 2009; Horsdal et al., 2009; Jørgensen et al., 2010, 2011; Juurlink, Gomes, Shah, & Mamdani, 2012; Nagendran et al., 2013). Our study extends the observed associations between IS use and adverse cardiovascular outcomes in two ways. First, we examined two adverse cardiovascular outcomes that have not been reported in previous observational studies: new onset atrial fibrillation and stroke. Second, we reported the risk of adverse cardiovascular outcomes for repaglinide, a nonsulfonylurea IS. Despite reporting similar observations, we believe that the present study has two advantages over previous observational studies. First,

we restricted our follow-up period to 30 days following the initial IHD hospitalization to limit the possibility exposure misclassification. Previous observational studies have followed patients for up to 5 years following a myocardial infarction whilst establishing sulfonylurea exposure on utilization in a brief period before admission (Arruda-Olson et al., 2009; Horsdal, Johnsen, Søndergaard, & Rungby, 2008; Jørgensen et al., 2011; Juurlink et al., 2012; Nagendran et al., 2013; Pantalone et al., 2010). Although Horsdal and colleagues (Horsdal et al., 2009) reported that 80% of patients surviving to 30 days post-myocardial infarction continued with the same preadmission sulfonylurea, the remaining studies do not report sulfonylurea use following the index myocardial infarction. Therefore, it is not clear if patients continued with the same sulfonylurea, switched to a different sulfonylurea or stopped using sulfonylureas altogether during the follow-up period. Second, we excluded patients with a history of the outcome of interest in our analyses, thus reducing the risk of protopathic bias. Previous studies included patients with a history of heart failure, myocardial infarction, angina or cardiac dysrhythmias (Jørgensen et al., 2010, 2011; Juurlink et al., 2012). Although differences in the prevalence of these conditions amongst the IS could be controlled for in an adjusted analysis, it would be difficult to determine if IS exposure preceded onset of the adverse cardiovascular outcome in these patients. Moreover, whether the decision to use a specific IS was based on pre-existing cardiovascular disease cannot be established. By excluding patients with a history of the adverse cardiovascular outcome, we were able to establish a plausible temporal relationship by identifying new onset rather than exacerbation of an existing disease. Our observations that the risk of adverse cardiovascular events following an IHD hospitalization is similar amongst gliclazide, glyburide, and repaglinide users appear to contradict the proposed pharmacologic differences amongst IS (Abdelmoneim et al., 2012; Gribble & Reimann, 2003). Our group and others have suggested that, based on information from in vitro and animal model studies, tissuespecific binding to sulfonylurea receptors may vary amongst IS. We have previously observed important differences in the risk of hospitalization or death attributable to acute coronary syndrome events between gliclazide and glyburide use (Abdelmoneim et al., 2014). However, the present study appears to suggest that the risk of adverse sequelae following these ischemic events is similar amongst IS. It is still not clear, therefore, if inhibition of KATP channels plays a significant role in the adverse cardiovascular effects of IS. Our observations should be interpreted in light of important limitations. First, we cannot rule out the possibility of residual confounding influencing the observed associations in our study. Although we were able to control for a comprehensive list of concurrent prescription medications and comorbidities, we did not have access to important clinical data, such as blood pressure, lipid levels, A1c, waist circumference and smoking status. More importantly, our study and others are unable to control for glucose levels. Although we have limited information on hypoglycemic events requiring hospitalization in our study, future studies should incorporate this important source of confounding in the analysis. Second, as with all observational studies, we made the assumption that dispensation records were a reasonable indicator of drug use. Our assumption might overestimate exposure, but we feel that the misclassification would be non-differential across gliclazide, glyburide and repaglinide users. Last, our study included patients 65 years and older, and therefore our observations are restricted to this patient group. For these reasons and considering the inherent limitations of observational studies when evaluating causality, our results could be considered hypothesis generating and should be verified in a properly designed randomized controlled trial. In conclusion, in this cohort of older patients with type 2 diabetes, the risk of adverse cardiovascular sequelae did not differ significantly

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amongst the IS used prior to an IHD hospitalization. The differences in tissue-specific receptor affinities and impairment of biological mechanisms observed through in vitro and animal models do not seem to translate into significant differences in observable clinical outcomes following an ischemic event at the population level. Financial support This study was funded through an operating grant provided by the Canadian Diabetes Association (OG-2-09-2693-SS). The CDA had no role in the analysis or interpretation of the data, or creation or submission of the manuscript. Mr. Abdelmoneim is supported by a Blanch/Wirtanen/Alberta Diabetes Foundation/Alberta Diabetes Institute Studentship for Diabetes Research and an Alliance for Canadian Health Outcomes Research in Diabetes (ACHORD) Studentship, funded by the Canadian Institutes for Health Research, reference # OGT-88588. Financial support This study was funded through an operating grant provided by the Canadian Diabetes Association (OG-2-09-2693-SS). The CDA had no role in the analysis or interpretation of the data, or creation or submission of the manuscript. Mr. Yuhao Huang was supported by a studentship through the Alberta Innovates Health Solutions. Mr. Ahmed Abdelmoneim is supported by studentships through the Alberta Diabetes Institute, the Alliance for Canadian Health Outcomes Research in Diabetes (ACHORD) Strategic Training Program in Diabetic Research, the Izaak Walton Killam Memorial Scholarship and a Canadian Diabetes Association Doctoral Studentship. Dr. Peter Light is holder of the Charles A. Allard Chair in Diabetes Research. Acknowledgment This study is based in part on data provided by Alberta Health. The interpretation and conclusions contained herein are those of the researchers and do not necessarily represent the views of the Government of Alberta. Neither the Government of Alberta nor Alberta Health expresses any opinion in relation to this study.

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