Post-authorization Safety Study (PASS) to Assess the Risk of Acute Pancreatitis in Type 2 Diabetes Mellitus (T2DM) Patients Newly Initiating Empagliflozin Compared to Other Oral Non-incretin/Non-sodium Glucose Co-transporter-2 Inhibitors (SGLT2)-Containing Glucose Lowering Drugs
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
 
Non-Interventional Study (NIS) Protocol 
 
Document Number:
c37704615-01
BI Study Number:
1245-0201
BI Investigational
Product(s):
Jardiance® (empagliflozin)
Title:
Post-authorization safety study (PASS) to assess the 
risk of acute pancreatitis in type 2 diabetes mellitus 
(T2DM) patients newly initiating empagliflozin 
compared to other oral non-incretin/non-sodium 
glucose 
co-transporter-2 
inhibitors 
(SGLT2)-
containing glucose lowering drugs
Brief lay title:
To assess the risk of acute pancreatitis in patients with 
type 2 diabetes mellitus treated with empagliflozin
Protocol version identifier:
1.0
Date of last version of protocol:
NA
PASS:
Yes
EU PAS register number:
EUPAS44267
Active substance:
A10BK03 Empagliflozin 
Medicinal product:
Jardiance® 
Product reference:
NA
Procedure number:
NA
Marketing authorization holder(s):

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Joint PASS:
No
Research question and objectives:
The main objective of the study is to compare the risk 
of acute pancreatitis in patients with type 2 diabetes 
mellitus (T2DM) newly initiating empagliflozin to 
that of patients newly initiating other oral non-
incretin/non-sodium
glucose 
co-transporter-2 
inhibitors (SGLT2i)-based glucose lowering drugs.  
Country(-ies) of study:
United States of America (USA)
Author:
Global Epidemiology, 
Boehringer Ingelheim International GmbH
Global 
Epidemiology, 
Boehringer Ingelheim International GmbH
In case of PASS, add:
MAH contact person:
In case of PASS, add:
<EU-QPPV:>
Boehringer Ingelheim International GmbH
Binger Straße 173
55216 Ingelheim am Rhein
Germany
In case of PASS, add:
<Signature of EU-QPPV:>
The signature of the EU-QPPV is provided 
electronically.
Date:
10 December 2021
Page 1 of 65
Proprietary confidential information
© 2021 Boehringer Ingelheim Group of companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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1.
TABLE OF CONTENTS
TITLE PAGE.............................................................................................................................1
1.
TABLE OF CONTENTS........................................................................................3
2.
LIST OF ABBREVIATIONS.................................................................................5
3.
RESPONSIBLE PARTIES.....................................................................................6
4.
ABSTRACT............................................................................................................7
5.
AMENDMENTS AND UPDATES......................................................................16
6.
MILESTONES......................................................................................................16
7.
RATIONALE AND BACKGROUND.................................................................17
8.
RESEARCH QUESTION AND OBJECTIVES...................................................18
9.
RESEARCH METHODS .....................................................................................19
9.1
STUDY DESIGN....................................................................................................19
9.2
SETTING ................................................................................................................19
9.2.1
Study sites......................................................................................................19
9.2.2
Study population............................................................................................19
9.2.3
Study visits ....................................................................................................21
9.2.4
Study discontinuation....................................................................................21
9.3
VARIABLES...........................................................................................................22
9.3.1
Exposures ......................................................................................................22
9.3.2
Outcomes.......................................................................................................23
9.3.3
Covariates......................................................................................................24
9.4
DATA SOURCES...................................................................................................25
9.5
STUDY SIZE ..........................................................................................................25
9.6
DATA MANAGEMENT........................................................................................26
9.7
DATA ANALYSIS .................................................................................................26
9.7.1
Definitions.....................................................................................................26
9.7.2
Propensity score approach.............................................................................29
9.7.3
Main analysis.................................................................................................30
9.7.4
Meta-analysis.................................................................................................32
9.7.6
Sensitivity analysis........................................................................................35
9.7.7
Handling of missing values...........................................................................35

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9.7.8
Safety Analysis..............................................................................................35
9.8
QUALITY CONTROL ...........................................................................................35
9.9
LIMITATIONS OF THE RESEARCH METHODS..............................................36
9.9.1
Data source....................................................................................................37
9.9.2
Confounding..................................................................................................38
9.9.3
Misclassification............................................................................................39
9.9.4
COVID-19 considerations.............................................................................39
9.9.5
Generalizability.............................................................................................41
9.10
OTHER ASPECTS..................................................................................................41
9.10.1
Data quality assurance...................................................................................41
9.10.2
Study records.................................................................................................41
9.10.3
Protocol deviations........................................................................................41
9.10.4
Compensation available to the patient in the event of study related injury ..41
10.
PROTECTION OF HUMAN SUBJECTS ...........................................................41
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT...............................................................................................................42
10.2
STATEMENT OF CONFIDENTIALITY..............................................................42
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ........................................................................................................42
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS .............................................................................................................42
13.
REFERENCES......................................................................................................43
13.1
PUBLISHED REFERENCES.................................................................................43
13.2
UNPUBLISHED REFERENCES...........................................................................50
14.
APPENDICES ......................................................................................................51
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.....................................................51
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .....................................52
ANNEX 3. LIST OF ICD 9 AND ICD 10 CODES FOR COHORT CREATION.............60
ANNEX 4. MEDICATION USED TO DEFINE EXPOSURES AND EXCLUSION 
CRITERIA OR CENSORING ..........................................................................61
ANNEX 5. REVIEWERS AND APPROVAL SIGNATURES..........................................63

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2.
LIST OF ABBREVIATIONS
BI
Boehringer Ingelheim
CI
Confidence Interval
CPRD
Clinical Practice Research Databases
CPT
Current Procedural Terminology codes
CTS-PS
Calendar-time specific (CTS) propensity scores (PS)
DPP-4i
Dipeptidyl peptidase 4 inhibitors
EMA
European Medicines Agency
ENCePP
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance
HbA1c
Hemoglobin A1c
HIPAA
Health Insurance Portability and Accountability Act of 1996
HR
Hazard Ratio
HCRU
Healthcare resource utilization
GLP-1 RA
Glucagon-like peptide-1 receptor agonist
ICD-9-CM
International Classification of Diseases, Ninth Revision, Clinical 
Modification
ICD-10-CM
International Classification of Diseases, Tenth Revision, Clinical 
Modification
ISPE
International Society for Pharmacoepidemiology
LOINC
Logical Observation Identifiers Names and Codes 
NIS
Non interventional study
NPV
Negative Predictive Value
NSAIDs
Non-steroidal anti-inflammatory drugs
Optum CDM
Optum Clinformatics® Data Mart
PASS
Post-authorization safety study
PPV
Positive Predictive Value
PS
Propensity scores 
PSUR
Periodic Safety Update Report
PY
Person-Year
RMP
Risk Management Plan
SEAP
Statistical Epidemiological Analysis Plan 

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SGLT2i
Sodium glucose co-transporter-2 inhibitor
SU
Sulfonylurea
T2DM
Type 2 diabetes mellitus
Truven 
Marketscan CCAE
Truven Marketscan Commercial Claims and Encounters 
Truven 
Marketscan 
MDCR
Truven Marketscan Medicare Supplemental (MDCR)
TZD
Thiazolidinediones
UK
United Kingdom
US
United States
3.
RESPONSIBLE PARTIES
Principal Investigators of the Protocol:
Boehringer Ingelheim:
!
 as of January 2020
!
 until September 2021
!
 until April 2020
!
 as of January 2021

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Jardiance® 
Name of active ingredient:
A10BK03 Empagliflozin
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
10/DEC/2021
1245-0201
1.0
NA
Title of 
study:
Post-authorization safety study (PASS) to assess the risk of acute pancreatitis in 
type 2 diabetes mellitus (T2DM) patients newly initiating empagliflozin compared 
to other oral non-incretin/non-sodium glucose co-transporter-2 inhibitors 
(SGLT2)-containing glucose lowering drugs
Rationale 
and 
background:
Empagliflozin is a sodium glucose co-transporter-2 inhibitor (SGLT2i) which 
promotes renal excretion of glucose and lowers elevated blood glucose levels in 
patients with T2DM [P14-09057]. Pancreatitis is defined as an important potential 
risk in the risk management plan (RMP) for empagliflozin. This post-authorization 
safety study (PASS) is voluntarily performed to assess the risk of acute pancreatitis 
in patients with T2DM newly initiating empagliflozin compared to the initiators of 
other oral non-incretin/non-SGLT2i–based glucose lowering drugs.  
Studies have shown that the risk of acute pancreatitis is higher in patients with 
T2DM and established cardiovascular disease (eCVD) than those without these
disorders [R10-6620, R10-2088, R21-0209]. In the past ten years, numerous 
studies assessed the association between pancreatitis and glucose lowering drugs in 
the United States (US) [R18-1760, P19-09574, R13-3873, R11-0776, R19-3424, 
P13-04390, P13-16900, R20-0777], Canada [P19-09574], United Kingdom (UK)
[P17-03843, P14-06737], Denmark [P15-05208], and in Asia [R19-3425, R19-
3426, R19-3427, R19-3428, R19-3429, R11-5180, P16-11950, R19-3430]. Certain 
diabetes drug classes, for instance incretin-containing medications including 
dipeptidyl peptidase 4 inhibitors (DPP-4i; such as sitagliptin, saxagliptin, 
linagliptin, alogliptin) and glucagon-like peptide-1 receptor agonists (GLP-1 RA; 
such as exenatide, liraglutide, lixisenatide, dulaglutide, semaglutide) [P13-15588]), 
have been associated with the risk of developing acute pancreatitis. Results vary
from protective to null associations to a 2-3 fold elevated risk of acute pancreatitis 
depending on the design, population, treatments and comparators studied [R18-
1760, P19-09574, R13-3873, R11-0776,  R19-3424, P13-04390, P13-16900, R20-
0777, P19-09574, P17-03843, P14-06737, P15-05208, R19-3425, R19-3426, R19-
3427, R19-3428, R19-3429, R11-5180, P16-11950, R19-3430]. Recently an 
observational study was conducted using large claims databases in the US (Truven 
Marketscan Commercial Claims and Encounters (CCAE) and Medicare
Supplemental (MDCR) Database, and Optum Extended Socio-Economic (SES)) to 
assess the risk of acute pancreatitis in T2DM patients newly exposed to 

Boehringer Ingelheim
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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Jardiance® 
Name of active ingredient:
A10BK03 Empagliflozin
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
10/DEC/2021
1245-0201
1.0
NA
canagliflozin compared to other oral glucose lowering drugs. Six different cohorts 
of new users of DPP-4is, GLP-1 RAs, sulfonylureas (SUs), thiazolidinediones 
(TZD), insulin, and other antihyperglycemic agents (AHA) were identified and 
compared separately with the new users of canagliflozin. Overall, no consistent 
difference in the risk of acute pancreatitis was observed when comparing 
canagliflozin with other oral glucose lowering drugs, not with regards to databases, 
nor with regards to different comparator groups [RRA-21430]. This inconsistent 
observation could have several reasons: 1) cohorts were not properly matched 
concerning previous use of AHA 2) cohorts were not matched with regards to 
acute pancreatitis risk factors e.g. gall stones 3) concomitant AHA treatment were 
allowed without restriction. Moreover, because of the heterogenous comparator 
and residual confounding, no conclusion could be made based on the study results.
Considering methodological challenges discussed above, this voluntary PASS was 
designed to investigate the risk of acute pancreatitis in new users of empagliflozin 
compared to the new users of other oral non-incretin/non-SGLT2i-containing
glucose lowering drugs. Comparison groups in this study are selected based on 
clinical guideline recommendations and current real-world patterns of use for oral 
glucose lowering drugs.
Research 
question and 
objectives:
The objective of the study is to compare the incidence rate of acute pancreatitis in 
T2DM patients initiating empagliflozin to new users of other oral non-
incretin/non-SGLT2i-containing glucose lowering drugs between 1 August 2014 
and the latest data-cut available in Marketscan (30 September 2020) and Optum 
(31 March 2021).
Study 
design:
Non interventional study (NIS) using existing data - new user active comparator 
cohort study
Population:
Truven Marketscan Commercial Claims and Encounters (CCAE), Truven 
Marketscan Medicare Supplemental (MDCR), and Optum Clinformatics® Data 
Mart [CDM] databases will be used in this study. All adults with a recorded 
diagnosis of T2DM who initiated empagliflozin or other oral non-incretin/non-
SGLT2i-containing glucose lowering drugs (metformin, SU, or TZD) between 1 
August 2014 and the latest data-cut available in Marketscan (30 September 2020) 
and Optum (31 March 2021.
Comparison groups are selected based on clinical guideline recommendations and 
current real-world patterns of use for oral glucose lowering drugs in patients with 
T2DM. First-line therapy in the US and most countries according to the guidelines 
is metformin. SUs, TZDs, and incretin therapies are next non-SGLT2i alternatives 

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Jardiance® 
Name of active ingredient:
A10BK03 Empagliflozin
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
10/DEC/2021
1245-0201
1.0
NA
for the treatment of T2DM, except for insulin. Several studies have reported 
associations between the use of incretin-based medications (including DPP-4is 
and GLP-1 RAs) and the risk of developing acute pancreatitis [P13-15588]. 
Hence, DPP-4is and GLP-1 RAs are excluded as comparators for this study.
Diabetes is a risk factor for acute pancreatitis [R10-6620, R10-2088], but there is 
limited information on the duration and severity of diabetes in the US claims 
databases. Creating comparison groups based on treatment line might be helpful to 
decrease residual confounding. Therefore, to assess the risk of acute pancreatitis 
we decided to conduct head-to-head comparative analyses (pending feasibility 
assessment and adequate sample size) using the separate therapy lines outlined 
below [P17-01404]:
!
Monotherapy: Empagliflozin vs. metformin 
!
Dual therapy: Empagliflozin vs. SU (both on a background of metformin)
!
Triple therapy: Empagliflozin vs. TZD (both on a background of metformin 
plus SU)
Separate analysis of the two databases within each treatment line is the ideal 
approach. However, if there are not enough study participants in the Optum and 
MarketScan databases in each therapy line, a meta-analysis of each therapy line 
will be conducted between Optum and MarketScan (pending heterogeneity and 
sample size assessments).
Other combinations of empagliflozin (e.g. empagliflozin on a background of SU 
or TZD, or empagliflozin on a background of SU and TZD) will not be assessed in 
this study due to the small sample size [Feasibility assessment report November 
2021, data on file].
Overall inclusion and exclusion criteria are listed below.:
General inclusion criteria: Patients must meet all of the following criteria to be 
eligible for inclusion in the study:
!
Patients >= 18 years old
!
A diagnosis of T2DM as demonstrated by at least one qualifying diagnosis 
code (International Classification of Diseases (ICD)-9-CM diagnosis code of 
250.x0 or 250.x2; ICD-10-CM diagnosis code of E11.x) from any encounter 
type recorded in the claims in the 6 months prior to the drug initiation.
!
Have at least 6 months of continuous registration in the database prior to 
initiation of empagliflozin or a comparator drug

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Jardiance® 
Name of active ingredient:
A10BK03 Empagliflozin
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
10/DEC/2021
1245-0201
1.0
NA
Exclusion criteria: Patients meeting any of the following criteria will be excluded 
from the study: 
!
Patients with missing or ambiguous age or sex information.
!
Use of a SGLT2i, DPP-4i or GLP-1 RA in the 6 months prior to study drug 
initiation.
!
Chronic use of insulin in the outpatient setting in the 6 months prior to the 
study drug initiation. This criterion will help to remove severe cases of 
diabetes and reduce the risk of residual confounding as diabetes is a risk 
factor for developing acute pancreatitis [R10-6620, R10-2088]. 
!
Patients with type 1 diabetes mellitus (T1DM) defined as at least 1 inpatient 
or outpatient ICD-9-CM diagnosis code of 250.x1 or 250.x3 or ICD-10-CM 
diagnosis code of E10.x in the 6 months prior to the study drug initiation.
!
Patients with secondary diabetes or gestational diabetes in the 6 months prior 
to the study drug initiation (codes are listed in Appendix 3).
!
Claims for acute or chronic pancreatitis, pancreatic cancer, or other disease of 
the pancreas any time prior to the study drug initiation.  
Treatment line specific inclusion criteria (if feasibility assessment would allow an 
adequately/sufficiently powered analysis) are:
!
For the monotherapy cohort, patients should be new users of empagliflozin or 
metformin (comparator). To quantify as a new user, no use of either of the 
two drugs (empagliflozin or metformin) in the previous 6 months is 
permitted.
!
For the dual therapy cohort, patients should be new users of empagliflozin (on 
a background of metformin) or new users of SU on a background of
metformin (comparator). To quantify as a new user, no use of either of the 
two drugs (empagliflozin or SUs) in the previous 6 months is permitted.
!
For the triple therapy cohort, patients should be new users of empagliflozin 
(on a background of metformin and SU) or new users of TZD on a 
background of metformin and SU (comparator). To quantify as a new user, no 
use of either of the 2 drugs (empagliflozin or TZDs) in the previous 6 months 
is permitted.
Variables:
Exposure variables will include: 
!
New therapy with empagliflozin for the treatment of T2DM (index medication 

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Jardiance® 
Name of active ingredient:
A10BK03 Empagliflozin
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
10/DEC/2021
1245-0201
1.0
NA
is empagliflozin)
-
As monotherapy
-
On a background of metformin
-
On a background of metformin and SU
!
New therapy with a non-incretin/non-SGLT2i-containing oral hypoglycaemic 
agent for the treatment of T2DM
-
Metformin monotherapy: index medication is metformin
-
SU (on a background of metformin): index medication is SU
-
TZD (on a background of metformin and SU): index medication is TZD
Fixed-dose combinations will be considered equivalent to free combination
regimens, e.g. Synjardy will be considered as dual therapy of empagliflozin on a 
background of metformin. Fixed dose combinations will be considered separately 
to describe switching, addition or stop, and for censoring patients.
Outcome: Primary outcome of this study is acute pancreatitis. 
The following algorithm will be used to identify cases of acute pancreatitis [R20-
3555, R20-3554]:
The presence of an acute pancreatitis diagnosis (ICD-9-CM 577.0 or ICD-10-CM 
K85) from any of the inpatient (not restricted to the primary diagnosis), outpatient, 
or emergency contacts diagnoses
AND
!
A lipase measure within +/- 7 days of the acute pancreatitis diagnosis (using 
Logical Observation Identifiers Names and Codes (LOINC) of 3040-3 and 
2572-6 or Current Procedural Terminology (CPT) code of 83690 for lipase)
AND
!
An abdominal ultrasound within +/- 7 days of the acute pancreatitis diagnosis 
(using CPT codes of 76700 or 76705)
Covariates:
Several baseline patient characteristics will be captured in the 6 months prior to the 
index date. Some of these covariates will be included as covariates in the 
propensity scores (PS) model.
!
Demographics
!
Comorbidity indexes: Elixhauser comorbidity index [R14-4775], Charlson 

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Jardiance® 
Name of active ingredient:
A10BK03 Empagliflozin
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
10/DEC/2021
1245-0201
1.0
NA
comorbidity index
!
Diabetes specific complications
!
Comorbidities
!
Prior/concomitant use of other oral glucose lowering drugs
!
Prior/concomitant use of drug(s) associated with acute pancreatitis:
-
α-methyldopa, azodisalicylate, bezafibrate, cannabis, carbimazole, 
codeine, cytosine, arabinoside, dapsone, enalapril, furosemide, 
isoniazid, 
mesalamine, 
metronidazole, 
pentamidine, 
pravastatin, 
procainamide, pyritonol, simvastatin, stibogluconate, sulfamethoxazole, 
sulinda, tetracycline, valproic acid, all trans-retinoic acid, amiodarone, 
azathioprine, clomiphene, dexamethasone, ifosfamide, lamivudine, 
losartan, 
lynesterol/methoxyethinylestradiol, 
Mercaptopurine, 
meglumine, 
methimazole, 
nelfinavir, 
norethindronate/mestranol, 
omeprazole, premarin, sulfamethazole, trimethoprimsulfamethazole, 
acetaminophen, chlorthiazide, clozapine, didanosine, erythromycin, 
estrogen, 
L-asparaginase, 
pegasparagase, 
propofol, 
tamoxifen, 
azathioprine, sulfonamides, tetracyclines, alpha-methyldopa
!
Prior/concomitant use of other medications (e.g. cardiovascular medications
etc.)
!
Other acute pancreatitis risk factors e.g. abdominal surgery, alcoholism and 
alcohol abuse, cystic fibrosis, gallstones and other gallbladder and biliary tract 
disorders, hyperparathyroidism, infection, injury to the abdomen, and lupus
!
Specific lab test results (when available)
Data 
sources:
Following claims databases in the US will be used in this study:
!
Truven Marketscan (CCAE and MDCR) Database
!
Optum Clinformatics® Data Mart [CDM]
Study size:
All patients with T2DM who newly initiate therapy with empagliflozin or study 
comparator and who meet the inclusion and exclusion criteria will be included in 
the analysis. 
Event rate of acute pancreatitis reported in patients with T2DM who are treated 
with canagliflozin was reported to be 2.2 per 1000 person-years (PY) [RRA-
21430].  This rate was used for sample size calculation using the formula of 
Farrington and Manning (maximum likelihood method) [R14-3295].

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Jardiance® 
Name of active ingredient:
A10BK03 Empagliflozin
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
10/DEC/2021
1245-0201
1.0
NA
Null hypothesis H0: ∀2 / ∀1 ≥1.5 (non-inferiority)
A single stage (fixed sample size) design was chosen. 
For specified # = 0.05 and rates ∀1 = 0.0022 and ∀2 = 0
.0022 (odds ratio of 1.000) the power (1 - ∃) is 80.0% if the test stages consist of 
the sample sizes given in the last two columns of the table.
The computation assumes an allocation ratio (n2/n1) = 1. It is assumed that all 
patients have 1 year of follow up.
Hazard 
ratio (HR)
sign. level     
one-sided      
#         
spent          
∃   
spent          
power           
achieved       
Observations 
per 
exposure 
group   
Overall 
observations  
1.5
0.0500         0.0500            -           
0.8000         34585.4
69170.8
ADDPLAN Adaptive Design Software 2019 and SAS 9.4 software (
, 
) were used to calculate the sample size.
Analysis of this study will be initiated as soon as a sufficient sample size to 
exclude a HR of 1.5 with 80% power is reached. Based on a feasibility assessment 
conducted in Optum and MarketScan databases using data between 1 August 2014 
and the latest data-cut available in MarketScan (30 September 2020) and Optum 
(31 March 2021), the dual-therapy cohort was reported with the highest number of 
empagliflozin initiators, therefore a meta-analysis of the dual therapy cohorts 
including the data from the MarketScan and Optum databases will be the main 
analysis of this study as it will be the only powered analysis.
Data 
analysis:
The index date in this study is defined as the date of the first recorded claim for a 
qualifying prescription as a new user. Patients are required to have at least 6 
months of continuous registration in the database prior to initiation of 
empagliflozin or a comparator drug (the look-back period). The look-back period 
includes the index date. The main analyses of this study will utilize a modified As-
Treated (AT) approach. 
Follow-up starts from the day after the index date until the first qualifying event 
has been met:
!
The earliest claim for acute pancreatitis
!
Addition of or switch to an incretin-based therapy (DPP-4is or GLP-1 RA) or 
insulin
!
Addition of or switch to the within treatment line comparator index drug (see 
section 9.7)

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Jardiance® 
Name of active ingredient:
A10BK03 Empagliflozin
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
10/DEC/2021
1245-0201
1.0
NA
!
Addition of or switch to an SGLT2i (in empagliflozin users, this would mean 
switch to a non-empagliflozin SGLT2i) (see section 9.7)
!
Discontinuation of index drug 
!
End of study (date of death, date of end of registration in the database, or 
study end date).
As a first step, a propensity score (PS) will be estimated for each cohort member at 
the index date, based on the values of the observed covariates during the look-back 
period. In this study, propensity scores will be estimated by conducting 
multivariable logistic regression modelling and incorporating measured potential 
predictors of therapy as independent variables and exposure group status 
(empagliflozin group vs. comparator) as the outcome. We will use PS matching to 
balance a number of covariates. Key advantages of PS matching are that large 
numbers of covariates that can be adjusted for even when studying infrequent 
outcomes, the achieved covariate balance can be documented, multiple outcomes 
can be studied after a single matching process, [R13-1120] and patients who 
cannot find comparable pairs will be implicitly dropped out of the analysis 
increasing the validity of findings [R17-1404].
The propensity score will be used to match patients in a 1:1 ratio using a nearest-
neighbor algorithm and calipers of width equal to 0.2 of the standard deviation of 
the logit of the propensity score [R13-3590, R18-2599, R16-1227]. A 1:n variable 
ratio matching will not be used as it involves several complications while 
providing only a minimal gain in estimation precision [R17-1267]. If balance is not 
achieved, the PS model will be refitted using interaction terms [R18-2599]. PS
balance achievement will be inspected by tabulating all patient characteristics by 
treatment status and by assessing the standardized differences. Any patient 
characteristics with a standardized difference of >10% will be considered for 
additional post-matching adjustment [R13-3590].
To account for patient characteristics changing over time, patients will be matched 
on the calendar quarter-year of initiation of the study medication. If we lose too 
many patients using this method, we may instead decide to match on year of 
initiation of index medication and then include calendar quarter-year variable in 
the PS model.
The incidence rates (per 1000 PY) and corresponding 95% confidence intervals 
(CI) of acute pancreatitis during the follow-up time will be calculated in each 
exposure group of interest in the unmatched and PS-matched cohorts. 

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Jardiance® 
Name of active ingredient:
A10BK03 Empagliflozin
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
10/DEC/2021
1245-0201
1.0
NA
Cox proportional hazards regression models based on time-to first acute 
pancreatitis event will be used to estimate hazard ratios (HR) and 95% CIs for each 
treatment line comparison of interest in the unmatched and PS-matched cohorts. 
Based on a feasibility assessment conducted in Optum and MarketScan databases 
using data between 1 August 2014 and the latest data-cut available in MarketSscan 
(30 September 2020) and Optum (31 March 2021), meta-analysis of the dual 
therapy cohorts including the data from the Marketscan MarketScan and Optum 
databases will be the main analysis of this study: 
!
Dual therapy: Empagliflozin vs. SU (both on a background of metformin)
All results will be presented for each database separately but if there is not enough 
sample size in each treatment line cohort in each database, after evaluating 
potential heterogeneity, meta-analysis techniques will be used to pool the treatment 
line cohorts of the 2 databases. Descriptive tables and all parameter estimates from 
the main and all sensitivity analyses will be pooled using meta-analytic methods 
assuming a fixed effects model, to avoid potential biases associated with random 
effects pooling in the context of few databases [R17-1410].
Milestones:
The study period is between 1 August 2014 (start of data collection) and the latest 
data-cut available in Marketscan (30 September 2020) and Optum (31 March 
2021) (end of data collection). In this multi database study, the start of data 
analysis will be in December 2021 and the final report will be available in Q3
2022.

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5.
AMENDMENTS AND UPDATES
None.
6.
MILESTONES
Milestone
Planned Date
IRB/IEC approval
Not applicable
Start of data collection
1 August 2014
End of data collection
30 September 2020 for Marketscan and 31 March 2021 for 
Optum
<Registration in the EU PAS 
register>
29 November 2021
Start of data analysis
Q4 2021
End of data analysis
Q2 2022
Final report of study results:
Q3 2022

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7.
RATIONALE AND BACKGROUND
Empagliflozin is an oral hypoglycemic agent belonging to the sodium glucose co-transporter-
2 inhibitor (SGLT2i) class, which promotes renal excretion of glucose and lowers elevated 
blood glucose levels in patients with type 2 diabetes mellitus (T2DM). Pancreatitis is defined 
as an important potential risk in the risk management plan (RMP) for empagliflozin. This 
post-authorization safety study (PASS) is voluntarily initiated by Boehringer Ingelheim (BI)
to assess the risk of acute pancreatitis in patients with T2DM newly initiating empagliflozin 
compared to initiators of other oral non-incretin/non-SGLT2i-containing hypoglycemic 
agents.  
Etiology and risk factors for pancreatitis
The most common etiologies for pancreatitis include cholelithiasis, alcohol use, and 
hypertriglyceridemia [P17-07372]. Other known causes of pancreatitis are trauma, surgery, 
cancer, anatomical variations of the pancreas and the pancreatic and biliary ducts, 
hypercalcemia, renal failure, and autoimmune disease [R20-0778]. Studies have shown that 
the risk of acute pancreatitis is higher in patients with T2DM and established cardiovascular 
disease (eCVD) than in patients without these disorders [R10-6620, R10-2088, R21-0209].
Different studies reported associations between the use of certain diabetes drug classes, for 
instance incretin-based medications (including dipeptidyl peptidase 4 inhibitors [DPP-4i; 
such as sitagliptin, saxagliptin, linagliptin, alogliptin] and glucagon-like peptide-1 receptor 
agonists [GLP-1 RA; such as exenatide, liraglutide, lixisenatide, dulaglutide, semaglutide] 
[P13-15588]) and the risk of developing acute pancreatitis. 
Potential mechanisms of action for drugs known to cause acute pancreatitis include 
pancreatic duct constriction (e.g. opioids) or cytotoxic effects that are either direct or due to 
accumulation of a toxic metabolite or intermediary [P16-02537]. 
Pancreatitis reoccurs in up to 25% of patients following hospital admission for their first 
episode of acute pancreatitis, with smoking and/or alcohol abuse demonstrated as 
predominant risk factors [R20-0778]. 
Epidemiology of pancreatitis
The incidence of acute pancreatitis in T2DM patients varies, with rates from the Clinical 
Practice Research Databases (CPRD) in the United Kingdom (UK) ranging between 54 and 
66 per 100,000 person-years (PY) and rates obtained from insurance claims databases in the 
United States (US) ranging between 422 and 560 per 100,000 PY [R10-5391, R10-6620, 
R10-2088]. The differences between these estimates may be due to the nature of the data 
sources and the populations studied. 

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In the past ten years, numerous studies assessed the association between pancreatitis and 
hypoglycemic agents in the US [R18-1760, P19-09574, R13-3873, R11-0776, R19-3424, 
P13-04390, P13-16900, R20-0777], Canada [P19-09574], UK [P17-03843, P14-06737], 
Denmark [P15-05208], and in Asia [R19-3425, R19-3426, R19-3427, R19-3428, R19-3429, 
R11-5180, P16-11950, R19-3430]. Certain diabetes drug classes, for instance incretin-
containing medications (including dipeptidyl peptidase 4 inhibitors (DPP-4i; such as 
sitagliptin, saxagliptin, linagliptin, alogliptin) and glucagon-like peptide-1 receptor agonists 
(GLP-1 RA; such as exenatide, liraglutide, lixisenatide, dulaglutide, semaglutide) [P13-
15588]), have been associated with the risk of developing acute pancreatitis. Results vary
from protective to null associations to 2-3 fold elevated risk of acute pancreatitis depending 
on the design, population, treatments and comparators studied [R18-1760, P19-09574, R13-
3873, R11-0776, R19-3424, P13-04390, P13-16900, R20-0777, P19-09574, P17-03843, P14-
06737, P15-05208, R19-3425, R19-3426, R19-3427, R19-3428, R19-3429, R11-5180, P16-
11950, R19-3430]. Recently an observational study was conducted using large claims 
databases in the US (Truven Marketscan Commercial Claims and Encounters (CCAE) and 
Medicare Supplemental (MDCR) Database, and Optum Extended Socio-Economic (SES)) to 
assess the risk of acute pancreatitis in T2DM patients newly exposed to canagliflozin 
compared to other oral hypoglycemic agents. Six different cohorts of new users of DPP-4is, 
GLP-1
RAs, sulfonylureas (SUs), thiazolidinediones (TZD), insulin, and other 
antihyperglycemic agents (AHA) were identified and compared separately with the new users 
of canagliflozin. Overall, no consistent difference in the risk of acute pancreatitis was 
observed when comparing canagliflozin with other oral glucose lowering drugs, not with 
regards to databases, nor with regards to different comparator groups [RRA-21430]. This 
inconsistent observation could have several reasons: 1) cohorts were not properly matched 
concerning previous use of AHA 2) cohorts were not matched with regards to acute 
pancreatitis risk factors e.g. gall stones 3) concomitant AHA treatment were allowed without
restriction. Moreover, because of the heterogenous comparator and residual confounding, no 
conclusion could be made based on the study results.
Considering methodological challenges discussed above, this voluntarily PASS was designed
to investigate the risk of acute pancreatitis in T2DM patients who initiated empagliflozin 
compared to new users of other oral non-incretin/non-SGLT2i-containing hypoglycemic
agents between 1 August 2014 and the latest data-cut available in MarketScan (30 September 
2020) and Optum (31 March 2021).
8.
RESEARCH QUESTION AND OBJECTIVES
This non-interventional cohort study using data from two large US claims databases will 
assess the risk of acute pancreatitis among T2DM patients initiating empagliflozin between 
from 1 August 2014 to the latest data-cut available in MarketScan (30 September 2020) and 
Optum (31 March 2021).  

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Primary Objective:
To compare the risk of acute pancreatitis in patients with T2DM newly initiating 
empagliflozin to that of patients newly initiating other oral non-incretin/non-SGLT2i-
containing hypoglycemic agents.  
9.
RESEARCH METHODS
9.1
STUDY DESIGN
This study will use a new user cohort design comparing patients with T2DM who initiated 
empagliflozin to those who initiated other oral non-incretin/non-SGLT2i-containing glucose 
lowering drugs, based on electronically recorded longitudinal data from 2 large US claims 
databases.
9.2
SETTING
Data from 2 large US claims databases (MarketScan and Optum) will be used (from 1 August 
2014 to the latest data-cut available in MarketScan (30 September 2020) and Optum (31 
March 2021),). The study implements an active comparator new user design and compares 
patients who newly initiate empagliflozin to those who newly initiate other oral non-
incretin/non-SGLT2i–containing glucose lowering drugs. Prior evidence suggested that 
incretin-based agents may be associated with an elevated risk of pancreatitis, therefore those 
agents will not be included in the analysis of this study. 
9.2.1
Study sites
See section 9.4. for data sources.
9.2.2
Study population
All patients with a recorded diagnosis of T2DM who initiated empagliflozin or other oral 
non-incretin/non-SGLT2i-containing glucose lowering drugs (metformin, SU, or TZD) 
between 1 August 2014 and 31 October 2020 will be selected from the Truven MarketScan 
Commercial Claims and Encounters (CCAE), Truven MarketScan Medicare Supplemental 
(MDCR), and Optum Clinformatics® Data Mart [CDM] databases.
Comparison groups were selected based on clinical guideline recommendations and current 
real-world patterns of use for oral glucose lowering drugs. First-line therapy in the US and 
most countries according to the guidelines is metformin. SUs, TZDs, and incretin therapies 
are the primary non-SGLT2i alternatives for the treatment of T2DM.  Several studies have 
reported associations between use of incretin-based medications (including dipeptidyl 
peptidase 4 inhibitors [DPP-4i; such as sitagliptin, saxagliptin, linagliptin, alogliptin] and 
glucagon-like peptide-1 receptor agonists [GLP-1 RA; such as exenatide, liraglutide, 
lixisenatide, dulaglutide, semaglutide] [P13-15588]) and risk of developing acute pancreatitis. 
Hence, DPP4is and GLP1RA are excluded from the comparators of this study. 

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Diabetes is a risk factor for acute pancreatitis [R10-6620, R10-2088], but there is limited 
information on the duration and severity of diabetes in the US claims databases. Creating 
comparison groups based on treatment line might be helpful to decrease residual 
confounding. Therefore, to assess the risk of acute pancreatitis we decided to conduct head-
to-head comparative analyses (pending feasibility assessment and adequate sample size) 
using the stratified therapy lines outlined below [P17-01404]:
!
Monotherapy:  Empagliflozin vs. metformin —> index medication is empagliflozin or 
metformin
!
Dual therapy: Empagliflozin vs. SU (both on a background of metformin) —> index 
medication is empagliflozin or SU
!
Triple therapy: Empagliflozin vs. TZD (both on a background of metformin plus SU) —> 
index medication is empagliflozin or TZD
Separate analysis of the two databases within each treatment line is the ideal approach. 
However, if there are not enough study participants in the Optum and MarkeScan databases 
in each therapy line, a meta-analysis of each therapy line will be conducted between Optum 
and MarketScan (pending heterogeneity and sample size assessments).
Other combinations of empagliflozin (e.g. empagliflozin on a background of SU or TZD, or 
empagliflozin on a background of SU and TZD) will not be assessed in this study due to the 
small sample size [Feasibility assessment report November 2021, data on file].
From a feasibility assessment conducted in November 2021, it is known that there are not 
enough study participants in the Optum and MarketScan database in each therapy line and the 
dual-therapy cohort was reported with the highest number of empagliflozin initiators. 
Therefore, a meta-analysis of the dual therapy cohorts including the data from the 
MarketScan MarketScan and Optum databases will be the main analysis of this study.
Due to low sample size and inadequate power, analysis of the mono- and triple therapy 
cohorts cannot be assessed.
Overall inclusion and exclusion criteria are listed below:
Inclusion criteria: Patients must meet all of the following criteria to be eligible for inclusion 
in the study:
!
Patients >= 18 years old
!
A diagnosis of T2DM as demonstrated by at least one qualifying diagnosis code 
(International Classification of Diseases (ICD)-9-CM diagnosis code of 250.x0 or 250.x2; 
ICD-10-CM diagnosis code of E11.x) from any encounter type recorded in the claims in 
the 6 months prior to the drug initiation.
!
Patients initiating empagliflozin (as monotherapy, on a background of metformin, or on a 
background of metformin and SU) or qualifying comparator (metformin monotherapy, 
SU on a background of metformin, or TZD on a background of metformin and SU) 
during the study period. 

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!
Have at least 6 months of continuous registration in the database prior to initiation of 
empagliflozin or a comparator drug
Exclusion criteria: Patients meeting any of the following criteria will be excluded from the 
study: 
!
Patients with missing or ambiguous age or sex information.
!
Use of a SGLT2i, DPP-4i or GLP-1 RA in the 6 months prior to study drug initiation.
!
Chronic use of insulin in the outpatient setting in the 6 months prior to the study drug 
initiation (definition is added to the SEAP). This criterion will help us to remove severe 
cases of diabetes and reduce the risk of residual confounding as diabetes is a risk factor 
for developing acute pancreatitis [R10-6620, R10-2088].
!
Patients with type 1 diabetes mellitus (T1DM) defined as at least 1 inpatient or outpatient 
International Classification of Diseases Ninth Revision, Clinical Modification (ICD-9-
CM) diagnosis code of 250.x1 or 250.x3 or International Classification of Diseases, Tenth 
Revision, Clinical Modification (ICD-10-CM) diagnosis code of E10.x in the 6 months 
prior to the study drug initiation.
!
Patients with secondary diabetes or gestational diabetes in the 6 months prior to the study 
drug initiation.
!
Claims for acute or chronic pancreatitis, pancreatic cancer, or other disease of the 
pancreas any time prior to the study drug initiation.  
Treatment line specific inclusion criteria (if feasibility assessment would allow a powered 
analysis) are:
!
For the monotherapy cohort, patients should be new users of empagliflozin or metformin 
(comparator). To quantify as a new user, no use of either of the two drugs (empaglifloin 
or metformin) in the previous 6 months is permitted.
!
For the dual therapy cohort, patients should be new users of empagliflozin (on a 
background of metformin) or new users of SU on a background of metformin 
(comparator). To quantify as a new user, no use of either of the two drugs (empagliflozin 
or SUs) in the previous 6 months is permitted.    
!
For the triple therapy cohort, patients should be new users of empagliflozin (on a 
background of metformin and SU) or new users of TZD on a background of metformin 
and SU (comparator). To quantify as a new user, no use of either of the 2 drugs 
(empagliflozin or TZDs) in the previous 6 months is permitted.      
All codes used in cohort creation are listed in Appendix 3 and 4.
9.2.3
Study visits
Not applicable.
9.2.4
Study discontinuation
Not applicable.

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9.3
VARIABLES
The variables that will be used in this study are described below.
9.3.1
Exposures
For this study, eligible patients will be identified from prescriptions/dispensings for the 
following study medications of interest (index medications):
Study drug will include: 
!
New therapy with empagliflozin (index medication) for the treatment of T2DM:
o
As monotherapy
o
As dual therapy (on a background of metformin)
o
As triple therapy (on a background of metformin and SU)
Comparator will be:
!
New therapy with an oral non-incretin/non-SGLT2i–containing hypoglycaemic agent for 
the treatment of T2DM:
o
As monotherapy (metformin monotherapy): index medication is metformin
o
As dual therapy (SU on a background of metformin): index medication is SU
o
As triple therapy (TZD on a background of metformin and SU): index medication 
is TZD
This leads to the following comparisons:
!
Monotherapy: Empagliflozin vs metformin
!
Dual therapy: Empagliflozin vs SU, both on background of metformin
!
Triple therapy: Empagliflozin vs TZD, both on a background of metformin and SU
Fixed-dose combinations will be considered equivalent to their free combination regimens. 
For instance, initiators of Synjardy will be categorized as dual therapy of empagliflozin. 
Combinations beyond triple therapy (i.e., use of 4+ glucose lowering drugs) will not be 
considered.
The index date is defined as the date of the first recorded claim for a qualifying prescription 
as a new user. Patients are required to have at least 6 months of continuous registration in the 
database prior to initiation of empagliflozin or a comparator drug (the look-back period). The 
look-back period was specified to confirm new medication use (i.e., having a first 
prescription claim for empagliflozin or other oral non-incretin/non-SGLT2i-containing
glucose lowering drugs without use in the prior 6 months) and describe baseline parameters, 
such as prior medical history and medications. The look-back period includes the index date.
The study will be conducted utilizing a modified “as-treated” approach. Study follow-up will
start the day after initiation of index medication and will continue until:
!
The first occurrence of the outcome 

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!
The date of end of continuous registration in the database
!
The date of death
!
The date of study end (31 October 2020)
!
The date of discontinuation of index medication (defined as the date of the last date of last 
dispensing + days supply + grace period). The grace period is a time period after 
exposure end during which observed outcomes are still attributed to the exposure. Grace 
period varies according to the specific outcome. In this study, for acute pancreatitis, we 
have 30 days [c18659315-02] grace period in the main analysis and 90 days in the 
sensitivity analysis [R18-1760, RRA-21430, P20-07536].
!
The date of switch of index medication to another hypoglycaemic agent (see section 
9.7.1. and SEAP)
!
The date of addition of incretin-based therapy (with continuation of index therapy)
!
The date of addition of SGLT2i (with continuation of index therapy)
!
The date of addition of insulin (with continuation of index therapy)
!
The date of addition of the within treatment line comparator index drug (with 
continuation of index therapy)
All definitions can be found in section 9.7.1. All codes used to define exposure variables are 
listed in Appendix 4.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
In this study we will use a modified version of an algorithm developed and validated in the 
with a sensitivity of 89.8% and a specificity of 79.4% [R20-
3555, R20-3554]. In the original algorithm, only the Logical Observation Identifiers Names 
and Codes (LOINC) were used for the lipase measurement but since these codes are only 
available for a subset of patients in Marketscan and Optum databases, to accommodate 
database needs, the equivalent Current Procedural Terminology (CPT) codes were added to 
the algorithm. This modified algorithm is:
!
The presence of an acute pancreatitis diagnosis from any of the inpatient (not restricted to 
the primary diagnosis), outpatient, or emergency contacts diagnoses (ICD-9-CM 577.0 or 
ICD-10-CM K85)
AND
!
A lipase measure within +/- 7 days of the acute pancreatitis diagnosis (using LOINC code
of 3040-3 and 2572-6 or CPT code of 83690 for lipase)
AND
!
An abdominal ultrasound (using CPT codes of 76700 and 76705) within +/- 7 days of the 
acute pancreatitis diagnosis
9.3.2.2
Secondary outcomes
None.

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9.3.3
Covariates
Several baseline patient characteristics will be captured in the 6 months prior to the index 
date. Some of these covariates will be included as covariates in the propensity scores (PS) 
model.
!
Demographics
!
Comorbidity indexes: Elixhauser comorbidity index [R14-4775], Charlson comorbidity 
index
!
Diabetes specific complications
!
Comorbidities (e.g. CVD [R21-0209])
!
Prior/concomitant use of other oral glucose lowering drugs
!
Prior/concomitant use of other drug(s) associated with acute pancreatitis [P08-00872]:
o
α-methyldopa, azodisalicylate, bezafibrate, cannabis, carbimazole, codeine, 
cytosine, arabinoside, dapsone, enalapril, furosemide, isoniazid, mesalamine, 
metronidazole, pentamidine, pravastatin, procainamide, pyritonol, simvastatin, 
stibogluconate, sulfamethoxazole, sulinda, tetracycline, valproic acid, all trans-
retinoic acid, amiodarone, azathioprine, clomiphene, dexamethasone, ifosfamide, 
lamivudine, 
losartan, 
lynesterol/methoxyethinylestradiol, 
Mercaptopurine, 
meglumine, methimazole, nelfinavir, norethindronate/mestranol, omeprazole, 
premarin, 
sulfamethazole, 
trimethoprimsulfamethazole, 
acetaminophen, 
chlorthiazide, clozapine, didanosine, erythromycin, estrogen, L-asparaginase, 
pegasparagase, propofol, tamoxifen, azathioprine, sulfonamides, tetracyclines, 
alpha-methyldopa
!
Prior/concomitant use of other medications (e.g. cardiovascular medications, full list is 
added in annex 5)
!
Other acute pancreatitis risk factors e.g. abdominal surgery, alcoholism and alcohol 
abuse, cystic fibrosis, gallstones and other gallbladder and biliary tract disorders, 
hyperparathyroidism, infection, injury to the abdomen, and lupus
!
Specific lab test results (when available, see below and SEAP)
!
Coronavirus (COVID-19) infection (this is applicable only to patients who have 2020 
data) during the baseline period and follow up
Given the nature of the databases, it will not be possible to include exposure to over-the-
counter medications as a covariate in the analysis.
The list of covariates is provided in Appendix 5 and all practical definitions and codes can be 
found in the statistical epidemiological analysis plan (SEAP).
Laboratory test results in a subset of patients:

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For a subset of about 40-50% of patients in Optum Clinformatics and 5-15% in MarketScan,
laboratory test results are available through linkage with two nationally operating lab test 
provider chains. Available laboratory test results during the 6 months prior to the index date 
will be identified using LOINC codes. After PS matching, if major imbalance is observed, 
patient characteristics with and without lab test results might be further explored as optional 
additional analysis. 
In case of multiple values available for a specific lab result, we will only consider the closest 
to the date of drug initiation. Laboratory tests of interests are provided in Annex 5 and 
include amylase (U/L); lipase (U/L); white cell count (G/L); red cell count (T/L); 
haemoglobin (g/L); haematocrit (%); thrombocyte (G/L); C-reactive protein (mg/L); 
creatinine (μmol/L), urea (mmol/L); serum bilirubin (μmol/L); GGT (mmol/L); GOT 
(mmol/L); GPT (mmol/L); ALP (mmol/L); uric acid (mmol/L); cholesterol (HDL, LDL) 
(mmol/L); triglycerides (mmol/L); serum protein (g/L); albumin (g/L)., C-peptide (pmol/L); 
HgbA1C (%); OGTT test glucose (mmol/L) and insulin level (pmol/L) at 0, 60 and 120 min 
[R20-3572].
9.4
DATA SOURCES
Two large US claims databases (Truven Marketscan Commercial Claims and Encounters 
(CCAE), Truven Marketscan Medicare Supplemental (MDCR), and Optum Clinformatics® 
Data Mart [CDM]) will be used in this study. Meta-analysis of the 2 databases might be used, 
when appropriate, to achieve the required study size. 
Main data elements from each database that will be used in this analysis include: 1) 
enrolment records, 2) pharmacy dispensing claims (dispensing date, National Drug Code 
[NDC] to determine product prescribed, quantity, and days of supply, and 3) medical claims 
(service date, diagnosis codes [ICD-9-CM, ICD-10-CM], procedure codes [Current 
Procedural Terminology (CPT)-4, ICD-9 Procedure Coding System (PCS), ICD-10-PCS], 
and laboratory test results (when available).
9.5
STUDY SIZE
All patients with T2DM who newly initiate therapy with empagliflozin or study comparator 
who meet the inclusion and exclusion criteria will be included in the analysis. 
Event rate of acute pancreatitis reported in patients with T2DM who are treated with 
canagliflozin was reported to be 2.2 per 1000 PY [RRA-21430]. This rate was used for 
sample size calculation using the formula of Farrington and Manning (maximum likelihood 
method) [R14-3295].
Null hypothesis H0: ∀2 / ∀1 ≥1.5 (non-inferiority)
A single stage (fixed sample size) design was chosen. 

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For specified # = 0.05 and rates ∀1 = 0.0022 and ∀2 = 0.0022 (odds ratio of 1.000) the power 
(1 - ∃) is 80.0% if the test stages consist of the sample sizes given in the last two columns of 
Table 1. 
The computation assumes an allocation ratio (n2/n1) = 1 (Table 1). It is assumed that all 
patients have 1 year of follow up.
Table 1
Number of empagliflozin initiators and empagliflozin-exposed person-years 
needed to detect a HR of 1.5 and 2.0 with a power of 80% and  = 0.05 under 1:1 
matching ratio
Hazard 
ratio 
(HR)
Information
rate
Bunds      
accept 
H0    
Bunds         
reject H0    
sign.level    
one-sided    
#         
spent       
∃   
spent    
power        
achieved    
Observations 
per exposure 
group   
Overall 
observations  
1.5
1.0    
1.645        1.645          0.0500         0.0500        -         0.8000        34585.4
69170.8
ADDPLAN Adaptive Design Software 2019 and SAS 9.4 software 
 
) were used to calculate the sample size.
Analysis of this study will be initiated as soon as a sufficient sample size to exclude a HR of 
1.5 with 80% power is reached. Based on a feasibility assessment conducted in Optum and 
MarketScan databases using data between 1 August 2014 and the latest data-cut available in 
MarketScan (30 September 2020) and Optum (31 March 2021), the dual-therapy cohort was 
reported with the highest number of empagliflozin initiators, therefore meta-analysis of the 
dual therapy cohorts including the data from the MarketScan and Optum databases will be the 
main analysis of this study as it will be the only powered analysis.
9.6
DATA MANAGEMENT
Data for this study is stored using the secured Instant Health Data (IHD) platform 
(https://www.bhei.com/product). Access to the data is granted by password to trained, BI 
personnel only. Full details of the data management plan are documented in a separate NIS-
Data Management and Review Plan (NIS-DMRP).
9.7
DATA ANALYSIS
The statistical analysis of this study is summarized below. Full details of the statistical 
analysis will be documented in the SEAP, which will be finalized before the start of data 
analysis. The final study cohorts will be created using the IHD platform and all analyses will 
be performed using SAS software (
9.7.1
Definitions
!
Index date: Date of the first recorded claim for a qualifying prescription of an index 
medication as a new user. 

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!
Follow-up: Starts from the day after the index date until the first qualifying event has 
been met (see Table 2 and 3). 
!
Look-back period: Patients are required to have at least 6 months of continuous 
registration in the database prior to initiation of an index medication. The look-back 
period is defined as 6 months prior to the index date and including the index date. The 
look-back period was specified to confirm new medication use (i.e. having a first 
prescription claim for empagliflozin or other oral non-incretin/non-SGLT2i-containing
hypoglycaemic without use of these medications in the prior 6 months) and describe 
baseline parameters, such as prior medical history and medications.
!
Grace period: 30 days in main analysis [c18659315-02] and 90 days [R18-1760, RRA-
21430, P20-07536] in sensitivity analysis.

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Table 2
Definitions for study end date
Reason for End of Study or 
censoring (earliest date of options 
below)
Definition for End Date
Acute pancreatitis event
Date of the first acute pancreatitis using ICD9 or 
ICD10 codes
Switch of index medication to 
another hypoglycaemic agent; see 
Table 3
Last date of known prescription coverage (date of 
last prescription fill plus days’ supply minus one 
day) and a grace period equal to 30 days. Exposure 
time will not extend past the date of the first 
prescription claim for the newly prescribed agent* 
Addition of incretin-based therapy 
(with continuation of index 
therapy)
Date of the prescription claim for the added incretin 
therapy
Addition of SGLT2i (with 
continuation of index therapy)
Date of the prescription claim for the added SGLT2i 
therapy
Addition of insulin (with 
continuation of index therapy)
Date of the prescription claim for the added insulin
therapy
Addition of the within treatment 
line comparator index drug; see 
Table 3 (with continuation of index 
therapy)
Date of the prescription claim for the added 
treatment line comparator index drug
Discontinuation of index drug 
Last date of known prescription coverage (date of 
last prescription fill plus days’ supply minus one 
day) and a grace period equal to 30 days* 
End of study data
Date of death#, Date of end of registration, Date of 
Study End
*The last date of known coverage may also be extended further to account for overlap periods – when a prescription is 
refilled before the previous supply was considered exhausted. Gaps between coverage and prescription refills that are less 
than the duration of each patient’s respective grace period will be considered continuous exposure time.
#It is not typically possible to ascertain all deaths that occur in studies based on administrative claims data. 
Discontinuation, addition, and switching are defined in the SEAP. Considerations for the 
follow up time and censoring after switching or addition are presented in Table 3.
Index drug for the monotherapy are empagliflozin and metformin, for the dual therapy
empagliflozin and SU, and for the triple therapy cohort empagliflozin and TZD.

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Table 3
Considerations for switching or adding during the follow-up period 
Treatment 
Line
Index Drug
Can Add (i.e. do not censor)
Cannot Add (i.e. 
censor at 
switch/addition)
Monotherapy
Empagliflozin
SU, TZD, and medications not 
mentioned in the next column
Metformin, 
incretins*, other 
SGLT2i, Insulin
Metformin
SU, TZD, and medications not 
mentioned in the next column
Any SGLT2i, 
incretins*, Insulin
Dual Therapy
Empagliflozin
TZD, and medications not 
mentioned in the next column
SU, incretins*, other 
SGLT2i, Insulin
SU
TZD, and medications not 
mentioned in the next column
Any SGLT2i, 
incretins*, Insulin
Triple Therapy
Empagliflozin
Medications not mentioned in 
the next column
TZD, incretins*, 
other SGLT2i, 
Insulin
TZD
Medications not mentioned in 
the next column
Any SGLT2i, 
incretins*, Insulin
*Incretins = DPP-4i or GLP-1 RA. 
In the dual therapy and triple therapy cohorts, if patients discontinue or switch medications 
other than index medication (e.g. metformin in the dual therapy cohort, and SU or metformin 
in the triple therapy cohort) they will not be censored; however, in the sensitivity analysis, 
this will be assessed by censoring those patients. Definitions for discontinuation, switch, and 
addition are mentioned in the SEAP.
9.7.2
Propensity score approach 
Decisions to begin a specific hypoglycaemic agent are influenced by demographic, medical, 
and clinical factors, and same factors might be associated with the outcomes of interest. The 
propensity score is the predicted probability of being assigned to a particular treatment 
conditional on a set of observed covariates. Because the models predict the probability of 
being treated with the exposure drug and not the probability of experiencing the outcome, a 
high number of variables can be used in the predicting regression model [P12-04844, R14-
5241, R14-5284, R14-5389].
Propensity scores for the comparison of empagliflozin vs. study comparator will be 
generated. Furthermore, given the different inclusion/exclusion criteria used for each 
treatment line cohort, the propensity scores will be cohort specific (i.e., propensity scores will 
be calculated for the monotherapy, dual therapy and triple therapy cohorts separately).

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As a first step, a propensity score is estimated for each cohort member at the index date, 
based on the values of the observed covariates during the look-back period. In this study, 
propensity scores will be estimated by conducting multivariable logistic regression modelling 
and incorporating measured potential predictors of therapy as independent variables and 
exposure group status (empagliflozin group vs. comparator) as the outcome. 
We will use PS matching to balance a number of covariates. Key advantages of PS matching 
are that large numbers of covariates can be adjusted even when studying infrequent 
outcomes, the achieved covariate balance can be documented, multiple outcomes can be 
studied after a single matching process, [R13-1120] and patients who cannot find comparable 
pairs will be implicitly dropped out of the analysis increasing the validity of findings [R17-
1404].
The propensity score will be used to match patients in a 1:1 ratio using a nearest-neighbor 
algorithm and calipers of width equal to 0.2 of the standard deviation of the logit of the 
estimated propensity score [R13-3590, R18-2599, R16-1227]. A 1:n variable ratio matching 
will not be used as it involves several complications while providing only a minimal gain in 
estimation precision [R17-1267]. If balance is not achieved, the PS model will be refitted 
using interaction terms [R18-2599]. PS balance achievement will be inspected by tabulating 
all patient characteristics by treatment status and by assessing the standardized differences. 
Any patient characteristics with a standardized difference of >10% will be considered for 
additional post-matching adjustment [R13-3590].
With the publication of EMPA-REG OUTCOME trial results in September 2015 and the 
approval of a separate indication to reduce the risk of cardiovascular death in adults with 
T2DM and established cardiovascular disease by the US FDA in December 2016, the 
characteristics of patients initiating empagliflozin has likely changed during the study period. 
To account for patient characteristics changing over time, patients will be matched on the 
calendar quarter-year of initiation of the study medication. If we lose too many patients using 
this method, we may instead decide to match on year of initiation of index medication and 
then include calendar quarter-year variable in the PS model.
9.7.3
Main analysis
The study will be conducted utilizing a modified “as-treated” approach. Users of 
empagliflozin or a comparator oral non-incretin/non-SGLT2i–containing hypoglycaemic 
agent will be considered exposed from the date of first prescription claim until earliest claim 
for acute pancreatitis or until one of the following censoring criteria have been met (Table 3):
!
The date of end of continuous registration in the database
!
The date of death
!
The date of study end
!
The date of discontinuation of index medication (defined as the date of the last date of last 
dispensing + days supply + grace period). The grace period is a time period after 
exposure end during which observed outcomes are still attributed to the exposure. Grace 

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period varies according to the specific outcome. In this study, for acute pancreatitis, we 
have 30 days grace period in the main analysis [c18659315-02] and 90 days in the 
sensitivity analysis [R18-1760, RRA-21430, P20-07536].
!
The date of switch of index medication to another hypoglycaemic agent
!
The date of addition of incretin-based therapy (with continuation of index therapy)
!
The date of addition of SGLT2i (with continuation of index therapy)
!
The date of addition of insulin (with continuation of index therapy)
!
The date of addition of the within treatment line comparator index drug (with 
continuation of index therapy)
For those who switch to an incretin therapy/SGLT2i, or switch to the within treatment line 
comparator, exposure duration will include the last date of known prescription coverage 
before the switch. For discontinuation of the index drug (with no prescription claim for a new 
hypoglycemic drug), exposure duration will include the last date of known prescription 
coverage (date of last prescription fill plus days’ supply minus one day) and a grace period 
equal to 30 days. The last date of known coverage may also be extended further to account 
for overlap periods – when a prescription is refilled before the previous supply was 
considered exhausted. Gaps between coverage and prescription refills that are less than the 
duration of each patient’s respective grace period will be considered continuous exposure 
time. For patients who switch, exposure time will not extend past the date of the first 
prescription claim for the newly prescribed switch agent.
For patients who add an incretin-based therapy, SGLT2i, or a within treatment line 
comparator index drug, their data will be censored on the date of the prescription claim for 
the added medication.  
Patients with chronic use of insulin at baseline (see SEAP for definition) in the outpatient 
setting during the follow-up period will be censored from the study. 
From a feasibility assessment conducted in November 2021, it is known that there are not 
enough study participants in the Optum and MarketScan database in each therapy line and the 
dual-therapy cohort was reported with the highest number of empagliflozin initiators. 
Therefore, a meta-analysis of the dual therapy cohorts including the data from the Marketscan 
MarketScan and Optum databases will be the main analysis of this study
Meta-analysis of different treatment line cohorts with the different comparators (first, second 
and third line) will not be conducted in this study as patients in these 3 cohorts will likely 
have very different profiles including different disease stages, and results would be difficult 
to interpret.
The incidence rates (per 1000 PY) and corresponding 95% confidence intervals (CI) of acute 
pancreatitis during the follow-up time will be calculated in each exposure group of interest in 
the unmatched and PS-matched cohorts. 

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All results will be presented for each database separately but if there is not enough sample 
size in each treatment line cohort in each database, after evaluating potential heterogeneity, 
meta-analysis techniques will be used to pool the 2 treatment line cohorts of the 2 databases. 
Descriptive tables and all parameter estimates from the main and all sensitivity analyses will 
be pooled using meta-analytic methods assuming a fixed effects model, to avoid potential 
biases associated with random effects pooling in the context of few databases [R17-1410].
Cox proportional hazards regression models based on time-to first acute pancreatitis event 
will be used to estimate hazard ratios (HR) and 95% CIs for each treatment line comparison 
of interest (in each database or in case of limited sample size a meta-analysis of 2 databases) 
in the unmatched and PS-matched cohorts. Proportionality hazard assumption will be 
checked using the log rank test.
9.7.4
Meta-analysis
After evaluating potential treatment effect heterogeneity we may pool results from the two 
databases. Descriptive tables and all parameter estimates from the main and all sensitivity 
analyses will be pooled using meta-analytic methods assuming a fixed effects model, since 
random effects pooling can be biased in the context of few databases [R17-1410]. Calculation 
of an overall mean/proportion/hazard ratio from two databases reporting a single 
mean/proportion/hazard ratio will use the inverse variance method for pooling [R02-0971]. 
To correct variance for potential duplicates in pooling two databases for the primary 
outcome, the following method will be used. The variance correction for overlapping samples 
when pooling multiple databases was described by 
 and 
[M20-
0016]. 
The formula for the variance is given by
	


= 

 + 

 + 2
Where
!
 and  are the weights applied to the two databases and  = 1 −
!

 and 
 are the variance estimates from both databases
!
 is the % of overlapping observations in the smaller dataset
!
 = (
 + 
 )/2 where  and  are the number of observations in both 
databases
Given that an exact overlap is not known between databases, estimates in 10% intervals will 
be used to assess varying degrees of variance in the pooled point estimates. The pooled 
analyses will be conducted using R package rmeta in R studio [R20-1986, M20-0016].

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9.7.6
Sensitivity analysis 
At least the following sensitivity analyses will be performed:
1. All analyses will be performed using an alternate outcome definition using the primary 
hospitalization discharge diagnosis only (ICD-9-CM 577.0 or ICD-10-CM K85 acute 
pancreatitis). 
2. Exclude cases with ICD-10 K85.2x (Biliary acute pancreatitis) and K85.3x (Alcohol 
induced acute pancreatitis) and also report the percentage of these cases in overall 
identified acute pancreatitis cases. 
3. Implement an intention-to-treat approach, where all users maintain assignment to their 
original treatment arm throughout a fixed follow-up period 12 months after first exposure. 
Users of empagliflozin or a comparator oral non-incretin/non-SGLT2i–containing glucose 
lowering drugs will be considered exposed from the date of first prescription claim 
(following a 6-month period without a prescription claim for their index medication) until 
earliest claim for acute pancreatitis or until one of the following censoring criteria have 
been met: death, end of registration, or study end. In this analysis, patients discontinuing 
therapy will not be censored. 
4. Subgroup analyses will be performed focusing on patients with and without history of 
eCVD in the 12 months prior to the index date
5. It is known that Diabetic ketoacidosis (DKA) can be complicated with pancreatitis. As a 
sensitivity analyses, cases with prior DKA will be excluded. 
6. In dual or triple therapy cohorts when the non-index medication (metformin) is 
discontinued or switched patients will be censored.
7. Considering grace period of 90 days for all medications.
9.7.7
Handling of missing values
The absence of a code for a condition will be interpreted as an absence of the event. If a study 
variable is totally missing from a database, it is excluded from the analysis of the pooled data.
If a variable is missing for only some of the patients a missing data category will be added 
and utilized in the analysis.
9.7.8
Safety Analysis
Not applicable based on secondary use of data without any potential that any employee of BI 
or agent working on behalf of BI will access individually identifiable patient data.
9.8
QUALITY CONTROL
The quality control, review, and monitoring plan are summarized below. Greater details are 
documented in the NIS-DMRP.

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All measures created, cohorts developed, statistical analyses implemented, and tables 
completed will be conducted by two analysts independently. After completing the whole 
analysis, each analyst will undergo quality control review for the other analyst’s work. The 
final results need to be consistent results from both analysts. 
This protocol will be strictly followed in the study. All changes to this protocol will be 
documented in protocol amendments.
All programs for data management and data analyses written by study statistician(s) will be 
self-documenting with comments about the data handling process, the population selection 
and the analysis performed by the program. The documentation will be sufficient for another 
statistician to be able to repeat the program. A statistician other than the one who writes the 
program will carry out quality control checks of these programs. The programming quality 
control (QC) will be performed for all programs related to the database, its individual datasets 
from different registers and statistical analyses. The QC will be documented with the 
following information:
!
Name of the program
!
Purpose of the program
!
Name of the programmer 
!
Validation status and date of validation
!
Updates and dates of updates
!
Name of the QC statistician 
!
QC findings or comments
!
Date of QC
The statistician responsible for the QC of a program will ensure that: 
!
The correct dataset and population is used
!
The analysis is carried out according to the SEAP 
!
The analysis results are consistent
!
The output is in line with the table shells in the SEAP
!
The analysis can be interpreted in both statistical and clinical terms
All QC findings by the QC statistician will be documented, and corrections are made to the 
programs accordingly. All changes are documented as updates to the original program. 
The raw dataset and statistical programs used for generating the data included in the final 
study report will be kept in electronic format and be available for auditing and inspection. 
9.9
LIMITATIONS OF THE RESEARCH METHODS
There are several methodological challenges when conducting epidemiologic studies to 
evaluate the association between glucose lowering drugs and outcomes of interest among 
patients with diabetes. These challenges include, but are not limited to, changes in treatment 
in response to advancing diabetes or due to adverse effects of specific drugs and time-varying 

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risk of an outcome [P12-13528, P14-17457, R14-4378]. Other limitations of the study are 
listed below.
9.9.1
Data source
The source claims data include limitations with respect to certainty of the capture of 
exposure, covariates, and outcomes. As a comprehensive insurance database, essentially all 
billable medical services will result in claims for reimbursement, so that the certainty of 
capture is tied to likelihood of a claim being submitted to the insurer.
Although duration of diabetes may represent a risk factor for the study outcome, this 
covariate will be incompletely captured since the patient history in the dataset is relatively 
short (at least 12 months, and an average of approximately 2 years), and a first claim within 
the database may not represent diabetes onset since the condition can be latent for some time 
and is typically not treated with hypoglycaemic medications at its diagnosis.
New initiators are operationally defined as patients with no use in the prior 6 months. This 
does not ensure, however, that patients have never used the drug of interest; the possibility 
remains that these patients were treated at some prior time point before they enrolled in their 
insurance plan.
There is potential for misclassification of dose based on healthcare utilization data, but the 
“days supply” field is expected to be fairly accurate. Similar concern may be present for 
exposure classification as well, but we expect the drug codes utilized in the data sources will 
appropriately represent the drug that is being classified.
Medication use in administrative healthcare databases is restricted to prescription drug 
medication. Consequently, the use of over-the counter (OTC) medications (e.g., OTC aspirin) 
is not captured. Additionally, the indication of a claim for prescription medications does not 
confirm whether the medication was actually taken by the patient or taken as prescribed.
It is estimated that two databases (MarketScan and Optum CDM) have about 10-15% overlap 
and it is not possible to identify duplicates and remove them between the two databases 
because patients are de-identified. It is not expected that this overlap impacts the results of 
this study because it will be much smaller in the study population. Furthermore, there is a 
sensitivity analysis to consider several scenarios of overlap in patients between the 
MarketScan and Optum (e.g., 0%, 10%, 20%, etc.), and 95% CIs of primary outcome will be 
adjusted accordingly.
Given that MarketScan and Optum CDM are claims databases, clinical laboratory data is only 
available for a small portion of enrolees (approximately 40-50% in Optum CDM and about 
5% in 
 MarketScan). 

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9.9.2
Confounding
A strength of this active-comparator new-user (rather than non-user) design is that it 
mitigates much of the confounding bias that can be prominent in comparative observational 
studies. Although use of propensity scores will facilitate the control of measured 
confounders, unmeasured and unidentified confounders could still introduce bias if they are 
differentially distributed among the exposed and comparator groups and are related to the 
outcome. As an example, use of over-the-counter medications will remain unmeasured in this 
study.
Confounding by indication or severity, also known as channelling bias, is a common bias in 
pharmacoepidemiology. Patients starting treatment with a newly marketed drug might have 
more severe disease than patients not taking the medication either because of self-selection or 
because of physician preference. They may also have a less severe form of the disease if 
physicians prefer to test new drugs with a less familiar safety profile in less severely affected 
patients. New medications may also be prescribed differentially by physicians who are “early 
adopters” of new technologies and who systematically treat more severely affected patients 
with the new medications. In previous empagliflozin safety studies, DPP-4 inhibitors were 
selected as the comparator group because these group of medications (relative to other oral 
hypoglycemic agents such as metformin and sulfonylureas) were recently introduced in the 
market. Therefore, using them as comparators reduces the risk of this type of bias. However, 
in this study, because of the existing association between DPP4 initiators and GLP1 agonists 
and study outcome (acute pancreatitis), these medications were not selected as comparators. 
Because of the possibility of channeling bias, the remaining oral hypoglycemic agents 
(metformin, SU, TZD) were not appropriate for a new user design that utilized a combined 
comparison group. A prevalent new user design was considered for this study, but because 
the long-term history of therapies for prevalent users is not typically available in the US 
claims databases, it was deemed more appropriate to use the active comparator new user 
design based on treatment lines as mentioned in section 9.3.1.
Study participants in the empagliflozin group will be 1:1 matched with comparators to 
account for confounders. After PS matching, study participants will be matched based on the 
calendar quarter year of the cohort entry to help minimize residual confounding. 
Although we will try to measure and include all available confounders in the PS models, 
some important variables e.g. alcohol abuse or smoking which are correlated with the 
outcome are not available for all study participants. Furthermore, study participants in the 
comparator groups are probably more prone to have lower socioeconomic status which is a 
potential for channelling bias that is not easy to detect in our study. These patients may also 
have different background risk for alcohol use and smoking.
Some of the outcome risk factors, e.g. infection, are only captured via hospital admission 
claims. Therefore, infections not resulting in hospitalization cannot be captured in this study 
and this increases the risk of residual confounding.

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9.9.3
Misclassification
To minimize misclassification of the recorded patient characteristics, previously validated 
algorithms or code-lists will be used whenever available. Code-lists were reviewed by 
qualified medical reviewers prior to implementation. A preliminary study to optimize and 
validate the algorithm for identification of cases of acute pancreatitis using ICD-9-CM and 
ICD-10-CM codes was conducted in the 
  
Some of the major risk factors for acute pancreatitis (e.g. alcohol use, obesity, biliary 
pathology not requiring reimbursement) are under-reported in claims databases. A similar 
limitation exists for use of medications known to cause acute or chronic pancreatitis, and it is 
impractical to account for all of these, even if the data are available. Conversely, the 
incidence of acute pancreatitis can be overestimated because providers may have used the 
acute pancreatitis code, abdominal ultrasound or serum lipase measurement to rule out the 
diagnosis of acute pancreatitis. To mitigate this risk, diagnosis for acute pancreatitis will be 
assessed using an algorithm that has been validated in the
and shown to have a sensitivity of 89.8% and a specificity of 79.4% [R20-3554]. However, 
this algorithm does not allow for etiological or pathophysiological description of the type of 
acute pancreatitis.
Further, the study utilizes a modified as-treated approach as the primary analysis, which 
could result in exclusion of some cases of acute pancreatitis due to censoring criteria (i.e., 
patients would be classified as not experiencing acute pancreatitis, but the event could have 
occurred after censoring). In order to address this, we will perform a sensitivity analysis using 
an ITT approach. This approach is more conservative and maintains drug classification 
similar to randomization; however, there is greater risk of exposure misclassification. 
Ultimately, however, this method will allow for evaluation of potentially additional cases of 
acute pancreatitis that transpire during the study period given the more limited censoring 
criteria.
Pancreatitis reoccurs in up to 25% of patients following hospital admission for their first 
episode of acute pancreatitis, with smoking and/or alcohol abuse demonstrated as 
predominant risk factors. Smoking and alcohol use could not be measured properly in the US 
claims databases. Moreover, the baseline period is only 6 months which might result in 
misclassification of some of recurrent acute pancreatitis events as the first event.
Another important topic to take into account is death which is considered a censoring event, 
but this information is not well captured in claims databases.
9.9.4
COVID-19 considerations
Although, there are a lot of unknown details around COVID-19 complications, a few small 
studies (mainly case reports) reported a possible link between COVID-19 infection and 
developing acute pancreatitis [R20-1531, R20-1532, R20-1536, R20-3357]. However, two 
recent observational studies conducted in the Netherlands and Italy suggested that the 
incidence of acute pancreatitis, as complication of COVID-19 infection, is very low and no 

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clear etiology was reported [R21-1729, R21-1730]. Therefore, as an optional analysis, 
characteristics of patients with acute pancreatitis which were observed after Q1 2020 in these 
2 databases will be evaluated to see if we can find any COVID-19 codes in the month prior to 
acute pancreatitis.

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9.9.5
Generalizability
Using a PS-matched analysis within a new user active comparator design decreases 
channelling bias, but also decreases the representativeness of the final patient cohort. The 
findings might not be generalizable to all patients with T2DM, especially those on treatment 
regimens that will not be included in this analysis.
The use of large claims data sources, such as MarketScan and Optum CDM, helps to ensure 
good representativeness of the US population. Although people over 65 years are under-
represented in the MarketScan databases, the use of the Optum CDM data will increase the 
proportion of people older than 65 years in the analysis.
9.10
OTHER ASPECTS
9.10.1
Data quality assurance
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by Institutional Review Board (IRBs) / Independent Ethics Committee 
(IECs) or by regulatory authorities. The quality assurance auditor will have access to all 
medical records, the investigator’s study-related files and correspondence, and the informed 
consent documentation of this study.
9.10.2
Study records
9.10.2.1
Source documents
Not applicable.
9.10.2.2
Direct access to source data and documents
Not applicable.
9.10.3
Protocol deviations
None.
9.10.4
Compensation available to the patient in the event of study related injury
Not applicable.
10.
PROTECTION OF HUMAN SUBJECTS
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, Guidelines for Good Pharmacoepidemiology Practice (GPP), and the 
relevant BI Standard Operating Procedures (SOPs). Standard medical care (prophylactic, 

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diagnostic and therapeutic procedures) remains the responsibility of the treating physician of 
the patient.
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This study will be registered with European Network of Centers for Pharmacoepidemiology 
and Pharmacovigilance (ENCePP) and on clinicaltrials.gov.
Data are de-identified and comply with the Health Insurance Portability and Accountability 
(HIPA) Act [R19-2252], and because this study will not involve the collection, use, or 
transmittal of individually identifiable data, Institutional Review Board review or approval is 
not required.
10.2
STATEMENT OF CONFIDENTIALITY
Not applicable.
11.
MANAGEMENT
AND 
REPORTING 
OF 
ADVERSE 
EVENTS/ADVERSE REACTIONS
Not applicable based on secondary use of data without any potential that any employee of BI 
or agent working on behalf of BI will access individually identifiable patient data.
12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The principal and co-investigators will lead the development of scientific manuscript(s) of the 
results to be published. A summary of the main results of the study, whether positive or 
negative, will always be made available to the public. As per Section V of Guidelines for 
Good Pharmacoepidemiology Practices
[R11-4318] and the Guideline on Good 
Pharmacovigilance Practices, Module VIII, Section B.7 [R13-5420], the outcome of a study 
will always be presented in an objective and truthful manner providing a comprehensive and 
accurate description of the findings. In no way shall the interpretation and presentation of the 
results be aimed towards any commercial, financial or personal interests. 
The principal and co-investigators will write the study report and the results will be reported 
within the earliest Periodic Benefit Risk Evaluation Report (PBRER). The study results will 
be published in the EU PAS registry. 

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
R10-6620
Girman CJ, Kou TD, Cai B, Alexander CM, O’Neill EA, Williams-
Herman DE, Katz L. Patients with type 2 diabetes mellitus have higher 
risk for acute pancreatitis compared with those without diabetes. Diab 
Obes Metab 2010; 12: 766-771.
P14-09057
Rosenstock J, Jelaska A, Frappin G, Salsali A, Kim G, Woerle HJ, Broedl
UC, EMPA-REG MDI Trial Investigators. Improved glucose control with
weight loss, lower insulin doses, and no increased hypoglycemia with
empagliflozin added to titrated multiple daily injections of insulin in obese
inadequately controlled type 2 diabetes. Diabetes Care 2014; 37: 1815 –
1823.
R10-2088
Noel RA, Patterson RE, Braun DK, Bloomgren GL. Increased risk of acute 
pancreatitis and biliary disease observed in patients with type 2 diabetes. 
Diab Care 2009; 32: 834-838.
R18-1760
Hong JL, Buse JB, Jonsson Funk M, Pate V, Sturmer T. The Risk of Acute 
Pancreatitis After Initiation of Dipeptidyl Peptidase 4 Inhibitors: Testing a 
Hypothesis of Subgroup Differences in Older U.S. Adults. Diabetes Care. 
2018;41(6):1196-1203.
P19-09574
Azoulay L, Filion KB, Platt RW, et al. Association Between Incretin-
Based Drugs and the Risk of Acute Pancreatitis. JAMA internal medicine. 
2016;176(10):1464-1473.
R13-3873
Wenten M, Gaebler JA, Hussein M, Pelletier EM, Smith DB, Girase P, 
Noel RA, Braun DK, Bloomgren GL. Relative risk of acute pancreatitis in 
initiators of exenatide twice daily compared with other anti-diabetic 
medications: a follow-up study. Diabet Med  2012; 29: 1412-1418.
R11-0776
Dore DD, Bloomgren GL, Wenten M, Hoffman C, Clifford CR, Quinn 
SG, Braun DK, Noel RA, Seeger JD. A cohort study of acute pancreatitis 
in relation to exenatide use. 2011 Diab Obes Metab 2011; 13: 559-566.
R19-3424
Li X, Zhang Z, Duke J. Glucagon‐like peptide 1‐based therapies and risk 
of pancreatitis: a self‐controlled case series analysis. 
Pharmacoepidemiology and drug safety. 2014;23(3):234-239.
P13-04390
Singh S, Chang H-Y, Richards TM, Weiner JP, Clark JM, Segal JB. 
Glucagonlike Peptide 1-Based Therapies and Risk of hospitalization for 
acute pancreatitis in type 2 diabetes mellitus. JAMA Intern Med 2013; 
doi:10.1001/jamainternmed.2013.2720.
P13-16900
Funch D, Gydesen H, Tornoe K, Major-Pedersen A, Chan KA. A 

Boehringer Ingelheim
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prospective, claims-based assessment of the risk of pancreatitis and 
pancreatic cancer with liraglutide compared to other antidiabetic drugs. 
Diabetes, obesity & metabolism. 2014;16(3):273-275.Romley 2012
P17-03843
Knapen LM. Essen JHM, Leufkens HB, van Erp NP, Keulemans YC, 
deJong RGPJ, de Vries F, de Bruin ML, Croes S. Use of incretin agents 
and risk of acute and chronic pancreatitis: a population-based cohort study. 
Diabet Obes Metab 2017; 19: 401-411.
P14-06737
Faillie JL, Azoulay L, Patenaude V, Hillaire-Buys D, Suissa S. Incretin 
based drugs and risk of acute pancreatitis in patients with type 2 diabetes: 
cohort study. Bmj. 2014;348:g2780.
P15-05208
Thomsen RW, Pedersen L, Moller N, Kahlert J, Beck-Nielsen H, Sorensen 
HT. Incretin-based therapy and risk of acute pancreatitis: a nationwide 
population-based case-control study. Diabetes Care. 2015;38(6):1089-
1098.
R19-3425
Shen H-N, Chang Y-H, Chen H-F, Lu C-L, Li C-Y. Increased risk of 
severe acute pancreatitis in patients with diabetes. Diabet Med 2012; 29: 
1419-1424
R19-3426
Kim YG, Kim S, Han SJ, Kim DJ, Lee KW, Kim HJ. Dipeptidyl 
Peptidase-4 Inhibitors and the Risk of Pancreatitis in Patients with Type 2 
Diabetes Mellitus: A Population-Based Cohort Study. Journal of diabetes 
research. 2018;2018:5246976
R19-3427
Chang CH, Lin JW, Chen ST, Lai MS, Chuang LM, Chang YC. 
Dipeptidyl Peptidase-4 Inhibitor Use Is Not Associated With Acute 
Pancreatitis in High-Risk Type 2 Diabetic Patients: A Nationwide Cohort 
Study. Medicine. 2016;95(7):e2603.
R19-3428
Yabe D, Kuwata H, Kaneko M, et al. Use of the Japanese health insurance 
claims database to assess the risk of acute pancreatitis in patients with 
diabetes: comparison of DPP-4 inhibitors with other oral antidiabetic 
drugs. Diabetes, obesity & metabolism. 2015;17(4):430-434.
R19-3429
Liao KF, Lin CL, Lai SW, Chen WC. Sitagliptin use and risk of acute 
pancreatitis in type 2 diabetes mellitus: A population-based case-control 
study in Taiwan. European journal of internal medicine. 2016;27:76-79.
R11-5180
Lai SW, Muo CH, Liao KF, Sung FC, Chen PC. Risk of acute pancreatitis 
in type 2 diabetes and risk reduction on anti-diabetic drugs: a population-
based cohort study in Taiwan. The American journal of gastroenterology. 
2011;106(9):1697-1704.
P16-11950
Tseng CM, Liao WC, Chang CY, et al. Incretin-based pharmacotherapy 
and risk of adverse pancreatic events in the ethnic Chinese with diabetes 
mellitus: A population-based study in Taiwan. Pancreatology : official 
journal of the International Association of Pancreatology (IAP)  [et al]. 

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001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
2017;17(1):76-82.
R19-3430
Chou HC, Chen WW, Hsiao FY. Acute pancreatitis in patients with type 2 
diabetes mellitus treated with dipeptidyl peptidase-4 inhibitors: a 
population-based nested case-control study. Drug safety. 2014;37(7):521-
528.
R14-1501
Moores K, Gilchrist B, Carnahan R, Abrams T. A systematic review of 
validated methods for identifying pancreatitis using administrative data. 
Pharmacoepidemiology and Drug Safety. 2012;21(S1):194-202.
R19-3492
Adamson DM, Chang S, Hansen LG. White Paper: Health Research Data 
for the Real World: The MarketScan Databases. Available at : 
https://www.researchgate.net/publication/281570301_Health_research_dat
a_for_the_real_world_The_MarketScan_databases
R19-3491
Watson Health. White Paper: The Truven Health MarketScan 
databases for health services researchers. Available at 
https://truvenhealth.com/portals/0/assets/2017_MarketScan_Databases_He
alth_Services_Researchers.pdfAccessed 25 October 2019.
R18-3672
Munch T, Christensen LB, Adelborg K, et al. Positive predictive values of 
ICD-10 codes to identify incident acute pancreatitis and incident primary 
malignancy in the Scandinavian national patient registries among women 
with postmenopausal osteoporosis. Clin Epidemiol. 2017;9:411-9
R19-3493
Optum, Inc.  Finding the right patients and investigators for faster clinical 
trials. Available at 
https://www.optum.com/content/dam/optum3/optum/en/resources/brochur
es/wf314692-optum-clinical-trial-solutions-brochure.pdf. Accessed 11 
February 2019.
R17-1267
Wang SV, Schneeweiss S, Rassen JA. Optimal matching ratios in drug 
safety surveillance. Epidemiology 25 (5), 772 - 773 (2014)
R20-0777
Romley JA, Goldman DP, Solomon M, McFadden D, Peters AL. 
Exenatide therapy and the risk of pancreatitis and pancreatic cancer in a 
privately insured population. Diabetes Technol Ther. 2012 
Oct;14(10):904-11. Epub 2012 Jul 30.
R14-4775
Quan H, Sundararajan V, Halfon P, Fong A, Burnand B, Luthi JC, 
Saunders LD, Beck CA, Feasby TE, Ghali WA. Coding algorithms for 
defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med 
Care. 2005 Nov;43(11):1130-9.
R20-0778
Ahmed Ali U, Issa Y, Hagenaars JC, et al. Risk of Recurrent Pancreatitis 
and Progression to Chronic Pancreatitis After a First Episode of Acute 
Pancreatitis. Clin Gastroenterol Hepatol. 2016;14(5):738–746. 
doi:10.1016/j.cgh.2015.12.040
P12-13528
Lo Re V, 3rd, Haynes K, Ming EE, Wood Ives J, Horne LN, Fortier K, et 

Boehringer Ingelheim
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c37704615-01
Proprietary confidential information © 2021BoehringerIngelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
al. Safety of saxagliptin: rationale for and design of a series of 
postmarketing observational studies. Pharmacoepidemiol Drug Saf 2012; 
21 (11): 1202-15.
P14-17457
Rawson NS. Review of the quality of observational studies of the 
association between rosiglitazone and acute myocardial infarction. J Popul 
Ther Clin Pharmacol 2014; 21 (2): e214-32.
R14-4378
Patorno E, Patrick AR, Garry EM, Schneeweiss S, Gillet VG, Bartels DB, 
et al. Observational studies of the association between glucose-lowering 
medications and cardiovascular outcomes: addressing methodological 
limitations. Diabetologia 2014; 57 (11): 2237-50.
R14-3295
Farrington CP, Manning G. Test statistics and sample size formulae for 
comparative binomial trials with null hypothesis of non-zero risk 
difference or non-unity relative risk. Stat Med 1990 ; 9(12) ; 1447-1454.
R20-1984
time varying covariates and meta-analysis references to be added 
R02-0971
DerSimonian R & Laird N (1986): Meta-analysis in clinical trials. 
Controlled Clinical Trials, 7,177–88; Barendregt JJ, Doi SA, Lee YY, 
Norman RE, Vos T (2013): Meta-analysis of prevalence. Journal of 
Epidemiology and Community Health, 67, 974–8
R20-1986
https://cran.r-project.org/web/packages/rmeta/rmeta.pdf
R18-2599
Austin PC. An introduction to propensity score methods for reducing the 
effects of confounding in observational studies. Multivariate Behav Res 
2011 ; 46; 399-424.    
R20-1531
Anand ER, Major C, Pickering O, Nelson M. Acute pancreatitis in a 
COVID-19 patient. British Journal of Surgery, Online ahead of print, 2020 
Apr 27, doi: 10.1002/bjs.11657; 2020. p. e182    
R20-1532
Hadi A, Werge M, Kristiansen KT, Pedersen UG, Karstensen JG, Novovic 
S, et al. Coronavirus disease-19 (COVID-19) associated with severe acute 
pancreatitis: case report on three family members. Pancreatology, Article 
in Press, Corrected Proof, Available online 5 May 2020, doi: 
10.1016/j.pan.2020.04.021; 2020. p. 665-667.    
R20-1533
Rajesh G, Nair AS, Narayanan VA, Balakrishnan V. Acute pancreatitis in 
viral infections, with possible progression to chronic pancreatitis. Indian J 
Gastroenterol 2008 ; 27(4) ; 162-164.    
R20-1534
Agzarian AE, Agzarian AY. Influenza A as a cause of acute pancreatitis: a 
case report. Proc UCLA Healthcare 2016 ; 20    
R20-3357
Liu F, Long X, Zou W, Fang M, Wu W, Li W, et al. Highly ACE2 
expression in pancreas may cause pancreas damage after SARS-CoV-2 
infection. doi: 10.1101/2020.02.28.20029181; 2020.    
R20-1536
Wang F, Wang H, Fan J, Zhang Y, Wang H, Zhao Q. Pancreatic injury 

Boehringer Ingelheim
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patterns in patients with COVID-19 pneumonia. Gastroenterology, Journal 
Pre-proof, Published online: April 01, 2020, doi: 10.1053/ 
j.gastro.2020.03.055; 2020. p. 367-370.    
P20-07536
Yuan Z, DeFalco F, Wang L, Hester L, Weaver J, Swerdel JN, et al. Acute 
pancreatitis risk in type 2 diabetes patients treated with canagliflozin 
versus other antihyperglycemic agents: an observational claims database 
study. Curr Med Res Opin 2020 ; 36(7) ; 1117-1124.    
R14-4278
Schneeweiss S, Rassen JA, Glynn RJ, Myers J, Daniel GW, Singer J, 
Solomon DH, Kim SY, Rothman KJ, Liu J, Avorn J. Supplementing 
claims data with outpatient laboratory test results to improve confounding 
adjustment in effectiveness studies of lipid-lowering treatments.    Med 
Res Methodol 2012 ; 12; 180    
R20-3573
Zhang Z, Kim HJ, Lonjon G, Zhu Y, AME Big-Data Clinical Trial 
Collaborative Group. Balance diagnostics after propensity score matching. 
Ann Transl Med 2019 ; 7(1) ; 16    
R13-3590
Austin PC. Optimal caliper widths for propensity-score matching when 
estimating differences in means and differences in proportions in 
observational studies. Pharm Stat 2011 ; 10(2) ; 150-161.    
R20-3572
Miko A, Eross B, Sarlos P, Hegyi P, Marta K, Pecsi D, et al. Observational 
longitudinal multicentre investigation of acute pancreatitis (GOULASH 
PLUS): follow-up of the GOULASH study, protocol. BMJ Open 2019 ; 9; 
e025500    
R16-1227
Austin PC. Balance diagnostics for comparing the distribution of baseline 
covariates between treatment groups in propensity-score matched samples. 
Stat Med 2009 ; 28(25) ; 3083-3107.    
R20-3555
Nichols GA, Deruaz-Luyet A, Iliev H, Brodovicz KG. Using electronic 
data to validate acute pancreatitis diagnoses. 36th Int Conf on 
Pharmacoepidemiology and Therapeutic Risk Management (ICPE 2020 
All Access) Virtual, 16 - 17 Sep 2020. Pharmacoepidemiol Drug Saf 2020 
; 29( Suppl 3) ; 301-302.    
R20-3554
Nichols GA, Deruaz-Luyet A, Illiev H, Brodovicz KG. Using electronic 
data to validate acute pancreatitis diagnoses. 36th Int Conf on 
Pharmacoepidemiology and Therapeutic Risk Management (ICPE 2020 
All Access) Virtual, 16 - 17 Sep 2020 (Poster). 2020    
R21-0209
Bexelius TS, Ljung R, Mattsson F, Lagergren J. Cardiovascular disease 
and risk of acute pancreatitis in a population-based study. Pancreas 2013 ; 
42(6) ; 1011-1015.
P17-01404
American Diabetes Association. Pharmacologic approaches to glycemic 
treatment. Diabetes Care 2017 ; 40(Suppl 1) ; S64-S74.
R21-1729
Bulthuis MC, Boxhoorn L, Beudel M, Elbers PWG, Kop MPM, Wanrooij 

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001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
RLJ van, et al. Acute pancreatitis in COVID-19 patients: true risk? Scand J 
Gastroenterol 2021 ; 56(5) ; 585-587.
R21-1730
Troncone E, Salvatori S, Sena G, Cristofaro E de, Alfieri N, Marafini I, et 
al. Low frequency of acute pancreatitis in hospitalized COVID-19 patients. 
Pancreas 2021 ; 50(3) ; 393-398.
P08-00872
Badalov N, Baradarian R, Iswara K, Li J, Steinberg W, Tenner S. Drug-
induced acute pancreatitis: an evidence-based review. Clin Gastroenterol 
Hepatol 2007 ; 5(6) ; 648-661.
P17-07372
Loehr JM, Dominguez-Munoz E, Rosendahl J, Besselink M, Mayerle J, 
Lerch MM, et al, HaPanEU/UEG Working Group. United European 
Gastroenterology evidence-based guidelines for the diagnosis and therapy 
of chronic pancreatitis (HaPanEU). United Eur Gastroenterol J 2017 ; 5(2) 
; 153-199.
P13-15588
Cohen D. Reports of pancreatitis are 20 - 30 times more likely with GLP-1 
drugs, analysis finds. Br Med J 2013 ; 346; f2607.
P16-02537
Hung WY, Lanfranco OA. Contemporary review of drug-induced 
pancreatitis: a different perspective. World J Gastrointest Pathophysiol 
2014 ; 5(4) ; 405-415.
P12-04844
Glynn RJ, Schneeweiss S, Sturmer T. Indications for propensity scores 
and review of their use in pharmacoepidemiology. Basic Clin Pharmacol 
Toxicol 2006 ; 98; 253-259.
R14-5241
Arbogast PG, Ray WA. Performance of disease risk scores, propensity 
scores, and traditional multivariable outcome regression in the presence of 
multiple confounders. Am J Epidemiol 2011 ; 174(5) ; 613-620.
R14-5389
Segal JB, Griswold M, Achy-Brou A, Herbert R, Bass EB, Dy SM, 
Millman AE, Wu AW, Frangakis CE. Using propensity scores 
subclassification to estimate effects of longitudinal treatments: an example 
using a new diabetes medication. Med Care 2007 ; 45(10) (Suppl 2) ; 
S149-S157.
R13-1120
Schneeweiss S. A basic study design for expedited safety signal evaluation 
based on electronic healthcare data. Pharmacoepidemiol Drug Saf 2010 ; 
19; 858-868.
R17-1404
Sturmer T, Rothman KJ, Avorn J, Glynn RJ. Treatment effects in the 
presence of unmeasured confounding: dealing with observations in the 
tails of the propensity score distribution - a simulation study. Am J 
Epidemiol 2010 ; 172(7) ; 843-854.
R17-1410
Borenstein M, Hedges L, Rothstein H. Meta-analysis: fixed effect vs. 
random effects. https://www.meta-analysis.com/downloads/M-
a_f_e_v_r_e_sv.pdf (access date: 18 April 2017); 2007.

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R17-2092
Patorno E, Everett BM, Goldfine AB, Glynn RJ, Liu J, Gopalakrishnan C, 
et al. Comparative cardiovascular safety of glucagon-like peptide-1 
receptor agonists versus other antidiabetic drugs in routine care: a cohort 
study. Diabetes Obes Metab 2016 ; 18(8) ; 755-765.
R11-2165
Schneeweiss S. Sensitivity analysis and external adjustment for 
unmeasured confounders in epidemiologic database studies of 
therapeutics. Pharmacoepidemiol Drug Saf 2006 ; 15; 291-303.
R19-2252
Hansen LG, Chang S. Health research data for the real world: the 
MarketScan databases. 
http://truvenhealth.com/portals/0/assets/PH_11238_0612_TEMP_MarketS
can_WP_FINAL. pdf (access date: 4 July 2019) ; Truven Health 
Analytics; 2011.
R11-4318
Guidelines for Good Pharmacoepidemiology Practices (GPP) (revision 2: 
April 2007). http://www.pharmacoepi.org/resources/guidelines_08027.cfm
(access date: 13 September 2011) ; Bethesda: International Society for 
Pharmacoepidemiology (ISPE); 2007.
R13-5420
European Medicines Agency (EMA)
Title: Guideline on good pharmacovigilance practices (GVP): module VIII 
- post-authorisation safety studies (rev 1) (19 April 2013, 
EMA/813938/2011 rev 1).
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guid
eline/2012/0 6/WC500129137.pdf (access date: 17 December 2013) ; 
European Medicines Agency (EMA), Heads of Medicines Agencies 
(HMA); 2013.
R10-5391
Garg R, Chen W, Pendergrass M. Acute pancreatitis in type 2 diabetes 
treated with exenatide or sitagliptin: a retrospective observational 
pharmacy claims analysis. Diabetes Care, Publish Ahead of Print, 
published online August 3, 2010; 2010. p. 2349-2354.
R14-5284
D'Agostino RB. Propensity scores in cardiovascular research. Circulation 
2007 ; 115; 2340-2343.

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13.2
UNPUBLISHED REFERENCES
RRA-21430 
Acute Pancreatitis in patients with T2D who are new users of 
canagliflozin as compared with new users of other antihypersglycemic 
agents: a retrospective cohort study using large claims databases in the 
United States. 01 Jun 2018 (
)
M20-0016
 Variance of combined effect estimate when samples are not 
independent. 2014.
c18659315-02
EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study 
program. Protocol version 2.0.

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14.
APPENDICES
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
None.

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Doc.Ref. EMA/540136/2009 
ENCePP Checklist for Study Protocols (Revision 4)
Adopted by the ENCePP Steering Group on 15/10/2018
The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP)
welcomes innovative designs and new methods of research. This Checklist has been developed by 
ENCePP to stimulate consideration of important principles when designing and writing a 
pharmacoepidemiological or pharmacovigilance study protocol. The Checklist
is intended to 
promote the quality of such studies, not their uniformity. The user is also referred to the ENCePP 
Guide on Methodological Standards in Pharmacoepidemiology, which reviews and gives direct 
electronic access to guidance for research in pharmacoepidemiology and pharmacovigilance.
For each question of the Checklist, the investigator should indicate whether or not it has been 
addressed in the study protocol. If the answer is “Yes”, the section number of the protocol where 
this issue has been discussed should be specified. It is possible that some questions do not apply 
to a particular study (for example, in the case of an innovative study design). In this case, the 
answer ‘N/A’ (Not Applicable) can be checked and the “Comments” field included for each section 
should be used to explain why. The “Comments” field can also be used to elaborate on a “No” 
answer. 
This Checklist should be included as an Annex by marketing authorisation holders when submitting 
the protocol of a non-interventional post-authorisation safety study (PASS) to a regulatory 
authority (see the Guidance on the format and content of the protocol of non-interventional post-
authorisation safety studies). The Checklist is a supporting document and does not replace the 
format of the protocol for PASS presented in the Guidance and Module VIII of the Good 
pharmacovigilance practices (GVP).
Study title:
Post-authorization safety study (PASS) to assess the risk of acute pancreatitis in type 2 
diabetes mellitus (T2DM) patients newly initiating empagliflozin compared to other 
oral non-incretin/non-sodium glucose co-transporter-2 inhibitors (SGLT2)-
containing glucose lowering drugs
EU PAS Register® number: EUPAS44267
Study reference number (if applicable):
Section 1: Milestones
Yes
No
N/A
Section
Number
1.1
Does the protocol specify timelines for 
1.1.1 Start of data collection1
6
                                                
1 Date from which information on the first study is first recorded in the study dataset or, in the case of secondary use of data, the date from 
which data extraction starts.

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Section 1: Milestones
Yes
No
N/A
Section
Number
1.1.2 End of data collection2
6
1.1.3 Progress report(s)
6
1.1.4 Interim report(s)
NA
1.1.5 Registration in the EU PAS Register®
6
1.1.6 Final report of study results.
6
Comments:
Section 2: Research question
Yes
No
N/
A
Section
Number
2.1
Does the formulation of the research question 
and objectives clearly explain: 
2.1.1 Why the study is conducted? (e.g. to address 
an important public health concern, a risk identified in 
the risk management plan, an emerging safety issue)
7
2.1.2 The objective(s) of the study?
8
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to be 
generalised)
9.2.2
2.1.4 Which hypothesis(-es) is (are) to be 
tested?
NA
2.1.5 If applicable, that there is no a priori
hypothesis?
NA
Comments:
Section 3: Study design
Yes
No
N/
A
Section 
Number
3.1
Is the study design described? (e.g. cohort, case-
control, cross-sectional, other design) 
9.1
3.2
Does the protocol specify whether the study is 
based on primary, secondary or combined data 
collection?
9.4
3.3
Does the protocol specify measures of 
occurrence? (e.g., rate, risk, prevalence)
9.7.3
3.4
Does the protocol specify measure(s) of 
association? (e.g. risk, odds ratio, excess risk, rate ratio, 
hazard ratio, risk/rate difference, number needed to harm 
(NNH))
9.7.3
                                                
2 Date from which the analytical dataset is completely available.

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Section 3: Study design
Yes
No
N/
A
Section 
Number
3.5
Does the protocol describe the approach for the 
collection and reporting of adverse 
events/adverse reactions? (e.g. adverse events that 
will not be collected in case of primary data collection)
11
Comments:
Section 4: Source and study populations
Yes
No
N/A
Section 
Number
4.1
Is the source population described?
9.2.2
4.2
Is the planned study population defined in terms 
of:
4.2.1 Study time period
9.2.2
4.2.2 Age and sex
9.2.2
4.2.3 Country of origin
9.2.2
4.2.4 Disease/indication
9.2.2
4.2.5 Duration of follow-up
9.2.2
4.3
Does the protocol define how the study 
population will be sampled from the source 
population? (e.g. event or inclusion/exclusion criteria)
9.2.2
Comments:
Section 5: Exposure definition and measurement
Yes
No
N/
A
Section
Number
5.1
Does the protocol describe how the study 
exposure is defined and measured?
(e.g. operational details for defining and categorising 
exposure, measurement of dose and duration of drug 
exposure)
9.3.1
5.2
Does the protocol address the validity of the 
exposure measurement? (e.g. precision, accuracy, use 
of validation sub-study)
NA
5.3
Is exposure categorised according to time 
windows?
9.3.1
5.4
Is intensity of exposure addressed? 
(e.g. dose, duration)
9.3.1
5.5
Is exposure categorised based on biological 
mechanism of action and taking into account the 
pharmacokinetics and pharmacodynamics of the 
drug?
NA

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Section 5: Exposure definition and measurement
Yes
No
N/
A
Section
Number
5.6
Is (are) (an) appropriate comparator(s) 
identified?
9.3.1
Comments:
Section 6: Outcome definition and measurement
Yes
No
N/
A
Section 
Number
6.1
Does the protocol specify the primary and 
secondary (if applicable) outcome(s) to be 
investigated?
9.3.2
6.2
Does the protocol describe how the outcomes
are defined and measured? 
9.3.2
6.3
Does the protocol address the validity of 
outcome measurement? (e.g. precision, accuracy, 
sensitivity, specificity, positive predictive value, use of 
validation sub-study)
9.3.2
6.4
Does the protocol describe specific outcomes 
relevant for Health Technology Assessment? 
(e.g. HRQoL, QALYs, DALYS, health care services utilisation, 
burden of disease or treatment, compliance, disease 
management)
NA
Comments:
Section 7: Bias
Yes
No
N/
A
Section
Number
7.1
Does the protocol address ways to measure
confounding? (e.g. confounding by indication)
9.7
7.2
Does the protocol address selection bias? (e.g. 
healthy user/adherer bias)
9.9
7.3
Does the protocol address information bias?
(e.g. misclassification of exposure and outcomes, time-
related bias)
9.9
Comments:
Section 8: Effect measure modification
Yes
No
N/A
Section
Number
8.1
Does the protocol address effect modifiers?
(e.g. collection of data on known effect modifiers, sub-group 
analyses, anticipated direction of effect) 
NA
Comments:

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Section 9: Data sources
Yes
No
N/A
Section 
Number
9.1
Does the protocol describe the data source(s) 
used in the study for the ascertainment of:
9.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-face 
interview)
9.3.1
9.1.2 Outcomes? (e.g. clinical records, laboratory 
markers or values, claims data, self-report, patient 
interview including scales and questionnaires, vital 
statistics)
9.3.2
9.1.3 Covariates and other characteristics?
9.3.3
9.2
Does the protocol describe the information 
available from the data source(s) on:
9.2.1 Exposure? (e.g. date of dispensing, drug quantity, 
dose, number of days of supply prescription, daily 
dosage,  prescriber)
9.3/9.4
9.2.2 Outcomes? (e.g. date of occurrence, multiple 
event, severity measures related to event)
9.3/9.4
9.2.3 Covariates and other characteristics?
(e.g. age, sex, clinical and drug use history, co-morbidity, 
co-medications, lifestyle)
9.3/9.4
9.3
Is a coding system described for: 
9.3.1 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC) Classification System)
SEAP
9.3.2 Outcomes? (e.g. International Classification of 
Diseases (ICD), Medical Dictionary for Regulatory 
Activities (MedDRA))
9.3
9.3.3 Covariates and other characteristics?
SEAP
9.4
Is a linkage method between data sources 
described? (e.g. based on a unique identifier or other)
NA
Comments:
Section 10: Analysis plan
Yes
No
N/
A
Section
Number
10.1 Are the statistical methods and the reason for 
their choice described? 
9.7
10.2 Is study size and/or statistical precision 
estimated?
9.5
10.3 Are descriptive analyses included?
9.7
10.4 Are stratified analyses included?
9.7
10.5 Does the plan describe methods for analytic 
control of confounding?
9.7

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Section 10: Analysis plan
Yes
No
N/
A
Section
Number
10.6 Does the plan describe methods for analytic 
control of outcome misclassification?
9.7
10.7 Does the plan describe methods for handling 
missing data?
9.7
10.8 Are relevant sensitivity analyses described?
9.7
Comments:
Section 11: Data management and quality 
control
Yes
No
N/
A
Section
Number
11.1 Does the protocol provide information on data 
storage? (e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving)
11.2 Are methods of quality assurance described?
11.3 Is there a system in place for independent 
review of study results? 
Comments:
Section 12: Limitations
Yes
No
N/
A
Section
Number
12.1 Does the protocol discuss the impact on the 
study results of:
12.1.1 Selection bias?
9.7
12.1.2 Information bias?
9.7
12.1.3 Residual/unmeasured confounding?
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods).
9.7
12.2 Does the protocol discuss study feasibility?
(e.g. study size, anticipated exposure uptake, duration of 
follow-up in a cohort study, patient recruitment, precision of 
the estimates)
9.5
Comments:
Section 13: Ethical/data protection issues
Yes
No
N/
A
Section
Number
13.1 Have requirements of Ethics Committee/ 
Institutional Review Board been described?

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Section 13: Ethical/data protection issues
Yes
No
N/
A
Section
Number
13.2 Has any outcome of an ethical review procedure 
been addressed?
13.3 Have data protection requirements been 
described?

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Comments:
Section 14: Amendments and deviations
Yes
No
N/
A
Section
Number
14.1 Does the protocol include a section to document 
amendments and deviations? 
Comments:
Section 15: Plans for communication of study 
results
Yes
No
N/
A
Section
Number
15.1 Are plans described for communicating study 
results (e.g. to regulatory authorities)?
12
15.2 Are plans described for disseminating study 
results externally, including publication?
12
Comments:
Name of the main author of the 
protocol:
Date: 29/11/2021
Signature: 

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ANNEX 3. LIST OF ICD 9 AND ICD 10 CODES FOR COHORT CREATION 
Condition
ICD 9 codes 1
ICD 10 codes 2
T1DM
250.X1, 250.X3
E10.xx
T2DM
250.X0, 250.X2
E11.xx
Gestational diabetes
648.8x
O24.1x, O24.4x
Secondary diabetes
249.xx
E08.xx, E09.xx,E13.xx
Acute pancreatitis
577.0
K85.xx
Chronic pancreatitis
577.1
K86.1 Other chronic pancreatitis
Pancreatitis cancer
157.xx
C25.xx
Other disease of
pancreatitis
577.2, 577.8, 577.9
K86.2, K86.3, K86.8x, K86.9
1. 2015 ICD-9-CM Diagnosis Codes: http://www.icd9data.com/2015/Volume1/default htm accessed at 14 March 2020
2. 2019 ICD-10-CM Codes: https://www.icd10data.com/ICD10CM/Codes accessed at 14 March 2020

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Position: Global TA 
Head Market Access* 
Name/Date:
_______________________
Signature: 
_______________
Position: Global TA 
Head PV RM*
Name/Date:
_______________________
Signature: 
_______________
Position: RWE CoE
Name/Date:
_______________________
Signature: 
_______________
Position: RWE CoE
Name/Date:
_______________________
Signature:
_______________
Position: RWE CoE
Name/Date:
_______________________
Signature: 
_______________
Position: NIS DM
Name/Date:
_______________________
Signature: 
_______________

 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
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