Post-authorisation Safety Study to Assess the Risk of Urinary Tract Malignancies in Relation to Empagliflozin Exposure in Patients With Type 2 Diabetes: a Multi-database European Study
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim

ABCD
Protocol for non-interventional studies based on existing data
TITLE PAGE
Document number:
c03856813-11
BI Study number:
1245.97
BI Investigational
Product(s):
Jardiance® (empagliflozin), Synjardy® 
(empagliflozin/metformin hydrochloride)
Title:
Post-authorisation safety study to assess the risk of urinary 
tract malignancies in relation to empagliflozin exposure in 
patients with type 2 diabetes: a multi-database European study
Protocol version 
identifier:
8.0
Date of last version of 
protocol:
07 July 2022
PASS:
Yes
EU PAS register 
number:
EUPAS16424 
Active substance:
A10BK03 empagliflozin, A10BD20 metformin and 
empagliflozin
Medicinal product:
Jardiance, Synjardy
Product reference:
EMEA/H/C/002677, EMEA/H/C/003770
Procedure number:
EMEA/H/C/002677/MEA; EMEA/H/C/003770/MEA
Joint PASS:
No
Research question and 
objectives:
The aim of the study is to assess the risk of urinary tract 
malignancies in patients initiating empagliflozin compared to 
patients initiating a DPP-4 inhibitor.

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Protocol for non-interventional studies based on existing data
BI Study Number 1245.97 
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Countries of study:
The United Kingdom, Sweden, and Finland
Authors:
Marketing 
authorisation holder(s):
MAH contact person:
EU-QPPV:
Signature of EU-
QPPV:
The signature of the EU-QPPV is provided electronically
Date:
17 May 2023
Page 1 of 111
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© 2023 Boehringer Ingelheim International GmbH or one or more of its affiliated 
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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BI Study Number 1245.97
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TABLE OF CONTENTS
TITLE PAGE.............................................................................................................................1
TABLE OF CONTENTS...........................................................................................................3
LIST OF TABLES.....................................................................................................................6
LIST OF FIGURES ...................................................................................................................7
1.
LIST OF ABBREVIATIONS............................................................................................8
2.
RESPONSIBLE PARTIES..............................................................................................10
3.
ABSTRACT.....................................................................................................................11
4.
AMENDMENTS AND UPDATES.................................................................................21
5.
MILESTONES.................................................................................................................26
6.
RATIONALE AND BACKGROUND............................................................................28
6.1
EPIDEMIOLOGY OF URINARY TRACT MALIGNANCIES IN 
DIABETES PATIENTS ......................................................................................................29
6.1.1
Incidence of urinary tract malignancies in the study population in the UK 
and Sweden observed in the fifth interim report of this study.........................................30
6.2
EPIDEMIOLOGY OF DIABETES AND DIABETES TREATMENT 
PATTERNS IN THE UK.....................................................................................................31
6.3
EPIDEMIOLOGY OF DIABETES AND DIABETES TREATMENT 
PATTERNS IN SWEDEN AND FINLAND ......................................................................32
6.4
RISK OF BLADDER CANCER IN PREVIOUS TRIALS OF SGLT-2 
INHIBITORS.......................................................................................................................32
6.5
RATIONALE FOR THE PROTOCOL AMENDMENT .............................32
7.
RESEARCH QUESTION AND OBJECTIVES .............................................................34
8.
RESEARCH METHODS ................................................................................................35
8.1
STUDY DESIGN..........................................................................................35
8.2
SETTING ......................................................................................................36
8.2.1
Study populations..........................................................................................36
8.2.2
Study period ..................................................................................................37
8.2.3
Index date ......................................................................................................37
8.2.4
Baseline and look-back (pre-index) period ...................................................37
8.2.5
Inclusion and exclusion criteria.....................................................................37
8.3
VARIABLES.................................................................................................38
8.3.1
Exposures ......................................................................................................39
8.3.2
Outcomes.......................................................................................................41

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8.3.2.1
Primary outcomes ........................................................................................41
8.3.3
Covariates......................................................................................................42
8.3.4
Censoring of follow-up time .........................................................................45
8.3.5
Follow-up time ..............................................................................................47
8.4
DATA SOURCES.........................................................................................48
8.4.1
The United Kingdom Clinical Practice Research Datalink (CPRD).............51
8.4.2
Swedish national registries............................................................................52
8.4.3
Finnish data sources ......................................................................................53
8.4.4
Additional potential data sources ..................................................................54
8.5
STUDY SIZE ................................................................................................54
8.6
DATA MANAGEMENT..............................................................................63
8.7
DATA ANALYSIS .......................................................................................63
8.7.1
Main analysis.................................................................................................63
8.7.1.1
Matching at index date.................................................................................63
8.7.1.2
As-treated (AT) analysis..............................................................................64
8.7.1.3
Population summary and descriptive analyses ............................................65
8.7.1.4
Comparative analyses ..................................................................................65
8.7.1.5
Variable selection.........................................................................................66
8.7.1.6
Monitoring of accrual of empagliflozin users..............................................66
8.7.1.7
Handling of missing data .............................................................................67
8.8
QUALITY CONTROL .................................................................................69
8.9
LIMITATIONS OF THE RESEARCH METHODS....................................70
8.9.1
Bias................................................................................................................71
8.9.2
Generalizability.............................................................................................71
9.
PROTECTION OF HUMAN SUBJECTS ......................................................................73
10.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS...........................................................................................................................74

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11.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS .75
12.
REFERENCES ............................................................................................................76
12.1
PUBLISHED REFERENCES.......................................................................76
12.2
UNPUBLISHsED REFERENCES................................................................80
13.
ANNEXURE................................................................................................................81
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.....................................................81
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .....................................82
ANNEX 3. READ CODES TO IDENTIFY TYPE 2 DIABETES .....................................88
ANNEX 4. CODES TO IDENTIFY EXPOSURE VARIABLES.....................................104
ANNEX 5. CODES TO IDENTIFY THE OUTCOME VARIABLES.............................107
ANNEX 6. COVARIATES TO BE CONSIDERED FOR INCLUSION IN THE 
PROPENSITY SCORE MODEL. .....................................................................................109
SIGNATURE.........................................................................................................................111

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LIST OF TABLES
Table 1. 
Crude incidence rates per 100,000 person-years for urinary tract cancers, 
Nordic countries 2013 and the UK 2012..........................................................29
Table 2. 
Patient counts by Glucose Lowering Medication category in the UK,
Sweden, and Finland ........................................................................................31
Table 3. 
Exposure definitions for primary and secondary analyses...............................40
Table 4. 
Baseline covariates to be considered for inclusion alternatively or 
simultaneously in primary, secondary, and further analyses ...........................43
Table 5. 
Minimum data requirements and data availability for the UK and the 
national registries in Sweden and Finland........................................................49
Table 6. 
Observed and expected number of patients eligible for inclusion in the 
study population, by study drug group (including fixed-dose combinations 
with metformin), by study country and overall, using an arithmetic growth 
assumption........................................................................................................55
Table 7. 
Power for different effect sizes for single-country analyses based on Cox 
models with a type 1 error probability of 5%, given country-level observed 
incidence rates, expected numbers of empagliflozin initiators, expected 
follow-ups, and expected matching ratios........................................................57
Table 8. 
Power of meta-analyses for a type 1 error probability of 5% for different 
effect sizes, given country-level observed incidence rates, expected number 
of empagliflozin initiators, expected average follow-ups, and expected 
matching ratios.................................................................................................57
Table 9.
Minimum detectable effect sizes (Hazard Ratios) given country-level 
observed incidence rate, expected sample sizes, expected average follow-
ups, and matching ratios for single-country analyses and meta-analyses for 
a type 1 error probability of 5%. ......................................................................58
Table 10. 
Required sample sizes in each study country to estimate different effect 
sizes for the three primary endpoints in the single-country analyses with at 
least 80% power and a type 1 error probability of 5%, given country-level 
incidence rates, expected average follow-ups, and expected matching ratios. 59
Table 11. 
Required sample sizes in each study country to estimate different effect 
sizes for the three primary endpoints in the meta- analyses with at least 80% 
power and a type 1 error probability of 5%, given country-level incidence
rates, expected average follow-ups, and expected matching ratios..................60
Table 12. 
Required follow-up time (years) to achieve 80% power in country-level 
analyses with a type 1 error probability of 5% for different effect sizes for
the three primary endpoints given country-level observed incidence rates, 
expected sample sizes, and expected matching ratios......................................61
Table 13. 
Required follow-up time (years) in each study country to achieve 80% 
power for the meta-analysis with a type 1 error probability of 5%for 
different effect sizes for the three primary endpoints given country-level 
observed incidence rates, expected sample sizes, and expected matching 
ratio...................................................................................................................62

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LIST OF FIGURES
Figure 1
Discontinuation of index drug due to stopping of index drug or switching of 
index drug. In the primary analysis follow-up is censored at treatment 
discontinuation. ................................................................................................47

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1.
LIST OF ABBREVIATIONS
AT
As-treated analysis
ATC
Anatomical Therapeutic Chemical Classification System
AvoHILMO
Register of primary health care visits
BI
Boehringer Ingelheim International GmbH
BMI
Body mass index
CI
Confidence interval
COPD
Chronic obstructive pulmonary disease
CPRD
Clinical Practice Research Datalink
CV
Cardiovascular
DDD
Defined daily dose
DPP-4
Dipeptidyl peptidase-4
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
EMR
Electronic medical record
ENCePP
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance
EU
European Union
FDA
Food and Drug Administration
GLP-1
Glucagon-like peptide-1
GP
General practitioner
GPP
Good Pharmacoepidemiology Practices
GPV
Good Pharmacovigilance Practices
HbA1c
Glycated haemoglobin A1c
HES
Hospital Episode Statistics
HF
Heart failure
HILMO
Care register for health care
HR
Hazard ratio
HUS
Helsinki University Hospital region
ICD-10
International classification of diseases
IPTW
Inverse-probability of treatment weights

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ITT
Intention-to-treat analysis
MI
Myocardial infarction
MSM
Marginal structural model
NCC
Nested case-control
NHS
National Health Service
NSAID
Non-steroidal anti-inflammatory drugs
ONS
Office for National Statistics
PASS
Post-safety study
PH
Proportional hazards
PID
Personal identification number
PS
Propensity score
PSUR
Periodic Safety Update Report
PY
Person-years
RMP
Risk management plan
RR
Relative risk
SEAP
Statistical/Epidemiological Analysis Plan
SGLT-2
Sodium glucose co-transporter-2
SID
Study identification number
SIR
Standardized incidence ratio
T2D
Type 2 diabetes mellitus
THIN
The Health Improvement Network database
UK
United Kingdom
US
United States
UT
Urinary tract
UTI
Urinary tract infection

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2.
RESPONSIBLE PARTIES
Principal investigator
Participating institutions
Sponsor
Boehringer Ingelheim International GmbH
The study investigators at 
 (
 Company) share responsibility with 
Boehringer Ingelheim International GmbH (BI) for the design of the study. The investigators 
are responsible for conducting the study in a manner that meets regulatory standards, 
conducting analyses, and preparing scientific reports. The study shall be conducted as 
described in the approved protocol. The authors will not develop or implement any deviation 
or change to the protocol without prior review by BI.
The financial sponsor of this study is BI. The sponsor is responsible to assure study progress. 
BI is also responsible for communicating with the European Medicines Agency (EMA) 
(called ‘the agency’) about the study protocol, the progress of the study, and study results.

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3.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of the finished medicinal 
product:
Jardiance®, Synjardy
Name of active ingredient:
Empagliflozin (A10BK03)
Metformin and empagliflozin (A10BD20)
Protocol date:
Study number/ 
Document number:
Version/Revision:
Version/Revision date:
16-Sep-2015
1245.97 / c03856813-10
8.0
17-May-2023
Title of study:
Post-authorisation safety study to assess the risk of urinary tract malignancies in 
relation to empagliflozin exposure in patients with type 2 diabetes: a multi-database 
European study
Rationale and 
background:
Empagliflozin is an oral blood glucose lowering drug belonging to the sodium glucose 
co-transporter-2 (SGLT-2) inhibitor class. SGLT-2 inhibitors promote the renal 
excretion of glucose and help lower elevated blood glucose levels in patients with type 
2 diabetes.
As a part of the risk management plans for empagliflozin and empagliflozin/metformin 
hydrochloride agreed upon by the European Medicines Agency (EMA), a post-
authorisation safety study (PASS) will be performed to assess the risk of urinary tract 
malignancies in patients initiating empagliflozin, compared to patients initiating 
dipeptidyl peptidase-4 (DPP-4) inhibitors. Prior to the development of the protocol for 
this study, a feasibility assessment of three databases in Europe (Clinical Practice 
Research Datalink (CPRD) and data with potential for linkage (Hospital Episode 
Statistics (HES), and Office for National Statistics (ONS) mortality statistics) in the 
United Kingdom (UK) and the national registers in Sweden and Finland) was 
performed with the aim to detail the minimum data requirements for the study and to 
assess, for each potential data source, the data quality, completeness of recorded 
information for urinary tract malignancies, and possibility of linkage with cancer 
registries, mortality registries, and other data sources. Initially, this study included two 
countries, the UK (CPRD GOLD) and Sweden, with follow-up until 31st December, 
2019. In order to increase the accumulated patient years and number of patients 
initiating the study drugs as well as accounting for the long latency period related to 
risk of malignancies, the study follow-up was first extended until 31st December, 2020 
and Finnish national registers were included. In this version of the protocol (Version 
7.0), CPRD Aurum was included and the study period extended to 31st December, 2021 
for both CPRD databases, further increasing the sample size and accumulated person-
years, and, consequently, increasing study power.

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BI Study Number 1245.97 
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Name of company:
Boehringer Ingelheim
Name of the finished medicinal 
product:
Jardiance®, Synjardy
Name of active ingredient:
Empagliflozin (A10BK03)
Metformin and empagliflozin (A10BD20)
Protocol date:
Study number/ 
Document number:
Version/Revision:
Version/Revision date:
16-Sep-2015
1245.97 / c03856813-10
8.0
17-May-2023
Research question 
and objectives:
Research Question:
The aim of the study is to assess the risk of urinary tract malignancies in patients 
initiating empagliflozin (free or fixed-dose combination) compared to patients initiating 
a DPP-4 inhibitor.
Primary objectives:
(i)
To estimate the adjusted hazard ratios (aHRs) and incidence rates (IRs) of all 
urinary tract cancers (bladder, renal and other urinary tract cancers) in 
patients initiating empagliflozin compared to patients initiating a DPP-4 
inhibitor
(ii) To estimate the aHRs and IRs of bladder cancer in patients initiating 
empagliflozin compared to patients initiating a DPP-4 inhibitor
(iii) To estimate the aHRs and IRs of renal cancer in patients initiating 
empagliflozin compared to patients initiating a DPP-4 inhibitor
Secondary objective:
To estimate the aHRs and IRs of each primary outcome (all urinary tract 
cancers, bladder cancer, renal cancer) with respect to:
a.
increasing cumulative dosage of empagliflozin exposure
b.
dosage of empagliflozin prescribed per use (e.g., 10mg vs 25mg of 
empagliflozin)
c.
time since first dose of empagliflozin exposure

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Protocol for non-interventional studies based on existing data
BI Study Number 1245.97 
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Proprietary confidential information © 2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of the finished medicinal 
product:
Jardiance®, Synjardy
Name of active ingredient:
Empagliflozin (A10BK03)
Metformin and empagliflozin (A10BD20)
Protocol date:
Study number/ 
Document number:
Version/Revision:
Version/Revision date:
16-Sep-2015
1245.97 / c03856813-10
8.0
17-May-2023
Study design:
This is a non-interventional, comparative, cohort safety study based on European 
healthcare databases. The databases for this study are constructed from linked 
prescription, hospital, general practitioner, cancer and death registration records. The 
study will use an “incident users” design and compare new users of empagliflozin to 
new users of DPP-4 inhibitors. The index date will be defined as the date on which each 
identified new user receives the index prescription for empagliflozin, or a DPP-4 
inhibitor. Follow-up will start 6 months after the index date (12 months in sensitivity 
analyses) to account for an empirical induction/promotion period. To minimize 
channelling bias, individuals will be matched with similar treatment and clinical history 
at index date by deriving propensity scores (PS). PS-matched cohorts will be derived 
for the comparison from the study base by matching patients who initiate empagliflozin 
with patients who initiate DPP-4 inhibitors at index date. To further gain power, the 
highest possible matching ratio  in each country-level dataset will be used. This will be 
implemented using a variable ratio approach in all countries, where exposed patients 
are matched to as many control patients as possible, up to a maximum of 3 matched 
controls.  Thus, an observational cohort is constructed to study the risk of urinary tract 
cancer among the two treatment groups. Depending on sample size, combination 
exposures with metformin will be accounted for through separate PS, stratification, or 
adjustment.

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Protocol for non-interventional studies based on existing data
BI Study Number 1245.97 
c03856813-11
Proprietary confidential information © 2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of the finished medicinal 
product:
Jardiance®, Synjardy
Name of active ingredient:
Empagliflozin (A10BK03)
Metformin and empagliflozin (A10BD20)
Protocol date:
Study number/ 
Document number:
Version/Revision:
Version/Revision date:
16-Sep-2015
1245.97 / c03856813-10
8.0
17-May-2023
Population:
The broad study population will include all patients from CPRD GOLD and CPRD 
Aurum in the UK and patients in the nationwide registers in Sweden and Finland, who 
have purchased at least one prescription of empagliflozin, or DPP-4 inhibitor drugs 
during the study period 2014-2020 (2021 for CPRD). Patients initiating empagliflozin, 
or DPP-4 inhibitor fixed-dose combinations with metformin will be included. 
Index date: Date of first purchase/prescription of empagliflozin, or a DPP-4 inhibitor 
during follow-up (2014-2020; 2014-2021 for CPRD). Patients initiating DPP-4 
inhibitor fixed-dose combinations with metformin will also be included. 
The study population will be selected from the broad study population with the 
following inclusion and exclusion criteria:
Inclusion criteria:

Diagnosis of type 2 diabetes (T2D)

Age over 18 years at index date

At least 1 year of membership in the database prior to index date; in CPRD, at 
least 1 year of continuous up-to-standard registration in the CPRD prior to the 
index date
Exclusion criteria: 

Patients with any cancer (excluding non-melanoma skin cancer) prior to index 
date

Diagnosis of type 1 diabetes or other specific non-T2D 

Use of any SGLT-2 inhibitor or any DPP-4 inhibitor (including free or fixed-
dose combinations) prior to index date

Use of fixed-dose combinations of SGLT-2 inhibitors with DPP-4 inhibitors 
Diagnosis of end stage renal disease or receipt of renal dialysis prior to index date
Variables:
Outcome variables:

All urinary tract cancers 

Bladder cancer 

Renal cancer 

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Protocol for non-interventional studies based on existing data
BI Study Number 1245.97 
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Proprietary confidential information © 2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of the finished medicinal 
product:
Jardiance®, Synjardy
Name of active ingredient:
Empagliflozin (A10BK03)
Metformin and empagliflozin (A10BD20)
Protocol date:
Study number/ 
Document number:
Version/Revision:
Version/Revision date:
16-Sep-2015
1245.97 / c03856813-10
8.0
17-May-2023
Definition of exposure: 
The primary definition of exposure for as-treated (AT) analysis is whether an individual 
is exposed to one of the following two index drug groups during the study period 
starting from 6 months after the index date and ending at treatment discontinuation of 
index drug:

Empagliflozin, or

DPP-4 inhibitor (sitagliptin, saxagliptin, linagliptin, vildagliptin, or 
alogliptin).
Patients initiating empagliflozin, or DPP-4 inhibitor in fixed-dose combinations with 
metformin will be included. Note that use of any of these drugs prior to index date is 
an exclusion criterion.
Secondary definitions of exposure include

cumulative dosage of empagliflozin use,

daily dosage of empagliflozin prescribed per use (10mg vs 25 mg), and

time since first dose of empagliflozin.
The following covariates, at a minimum, will be accounted for as variables for exact or 
PS matching and stratification, and in sensitivity analyses, in the risk set definition in 
nested-case-control (NCC) design and as covariates to derive inverse-probability of 
treatment weight (IPTW) in marginal structural models (MSMs) and/or model 
adjustment. These covariates will be identified based on codes recorded prior to the 
index date (exclusive of index date) unless otherwise specified below.

Socio-demographic variables (age, sex, year of index date, length of available 
look-back time)

Concomitant medications (insulin use, other oral glucose lowering medication 
use, diabetes treatment complexity, other non-diabetes medications)

Comorbidities such as
o
Diabetic complications (including latest HbA1c value)
o
Urinary tract-related diseases
o
Cardiovascular diseases

BMI, smoking, alcohol use (closest to index date)
Additional covariates will be included according to data availability are, such as 
socioeconomic position and laboratory measurements.

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Protocol for non-interventional studies based on existing data
BI Study Number 1245.97 
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Proprietary confidential information © 2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of the finished medicinal 
product:
Jardiance®, Synjardy
Name of active ingredient:
Empagliflozin (A10BK03)
Metformin and empagliflozin (A10BD20)
Protocol date:
Study number/ 
Document number:
Version/Revision:
Version/Revision date:
16-Sep-2015
1245.97 / c03856813-10
8.0
17-May-2023
Data sources:
The following databases are country-specific data sources from which a linked master 
database for each country will be constructed.
The UK: CPRD GOLD and CPRD Aurum optionally complemented with HES 
(Outpatient data, and Admitted Patient Care data), and ONS mortality sources.
Sweden: The following nationwide population-based registers will be accessed: The 
National Patient Register, the Swedish Prescribed Drug Register, the Swedish Cancer 
Register, the Causes of Death Register, the National Diabetes Register, and the 
Longitudinal integration database for health insurance and labor market studies.
Finland: The following nationwide population-based registers will be accessed: the 
Finnish prescription register/the registry for reimbursed medications, the Care register 
for health care (HILMO), the Register of primary health care visits (AvoHILMO), and 
the Finnish cancer register. Additionally, four regional electronic medical record 
(EMR) databases will be accessed to obtain information on laboratory measures. 
Initially, the country-level datasets will be analysed separately. Thereafter, country-
level estimates will be pooled using meta-analysis techniques to gain power and 
produce as narrow confidence intervals (CI) as possible.
If patient numbers accumulating in these data sources are below the expected counts, 
alternatives will be evaluated as described in Section 8.4.4

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Name of company:
Boehringer Ingelheim
Name of the finished medicinal 
product:
Jardiance®, Synjardy
Name of active ingredient:
Empagliflozin (A10BK03)
Metformin and empagliflozin (A10BD20)
Protocol date:
Study number/ 
Document number:
Version/Revision:
Version/Revision date:
16-Sep-2015
1245.97 / c03856813-10
8.0
17-May-2023
Study size:
The study size will be driven by the uptake of empagliflozin and DPP-4 inhibitors for 
the treatment of T2D to improve glycaemic control in adults in the UK, Sweden, and 
Finland. Study-size and power computations were carried out for the meta-analysis of 
the primary outcomes. Originally, it was expected that by the end of 2019, 
approximately 18,000 empagliflozin-treated patients will accumulate in the CPRD and 
Swedish databases. However, based on the conservative estimates from the third 
monitoring report (2019), the expected sample size was higher than anticipated with 
approximately 25,000 empagliflozin initiators eligible for inclusion in the study. 
Further, additional 38,000 patients were expected by the end of 2020 with the inclusion 
of Finnish databases, for a total of approximately 78,000 by the end of the study period. 
Updated estimates in the fifth interim report (2021) indicated that a total of 57,000 
empagliflozin initiators were expected to be eligible for inclusion in the study in CPRD-
GOLD, Sweden, and Finland by the end 2020. New estimations including the inclusion 
of CPRD-Aurum and the extension of the study period to the end of 2021 for both 
CPRD databases suggest that a total of 67,490 empagliflozin initiators could be eligible 
for inclusion across all three countries. Furthermore, the observed numbers of patients 
initiating DPP-4 inhibitors in each country suggest that achievable matching ratios 
would be 1:3 in UK-CPRD, 1:1 in Sweden, and 1:2 in Finland.
Power to detect relative risks of  1.5 and 2 was determined at the meta-analysis level, 
for each of the study outcomes, based on the expected number of individuals exposed 
to empagliflozin eligible for inclusion in the study for each country (approximately 
16,887 in UK-CPRD (GOLD and Aurum), 32,334 in Sweden, and 18,269 in Finland) 
and the observed IRs of urinary tract cancers, bladder cancer and renal cancer in 
country-level study populations as reported in the fifth interim report (UK-CPRD: 
111.5, 66.7, 26.5 per 100 000 PY: Sweden: 164.5, 104.1, 58.0  per 100 000 PY;  
Finland: 161.5, 86.8, 71.6  per 100 000 PY; ,respectively for urinary tract cancer, 
bladder cancer and renal cancer). Power calculations performed for the primary 
comparison between empagliflozin users and DPP-4 inhibitors indicated that the 
power at the meta-analysis level for detecting a hazard ratio of 1.5 would be 93.6% 
for urinary tract cancer and 84,0% for bladder cancer. Power for detecting a hazard 
ratio of 2.0 for renal cancer would be 97.0%. 

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Name of company:
Boehringer Ingelheim
Name of the finished medicinal 
product:
Jardiance®, Synjardy
Name of active ingredient:
Empagliflozin (A10BK03)
Metformin and empagliflozin (A10BD20)
Protocol date:
Study number/ 
Document number:
Version/Revision:
Version/Revision date:
16-Sep-2015
1245.97 / c03856813-10
8.0
17-May-2023
In addition, anticipated study sample size would ensure sufficient power for the meta-
analysis to detect the targeted effect size of < 1.6 for urinary tract cancers and bladder 
cancer and the targeted effect size of < 2.0 for renal cancer, with 80% power under the 
expected matching ratios in each study country.
Results from the second and third interim analysis showed that not enough patients will 
have accumulated in the UK CPRD or Swedish registers by the planned end of data 
collection to reach the desired sample size. For this reason, the protocol was first 
amended to expand the study population by including data from the Finnish national 
registries and extend the study period until 31st December 2020. Following results from 
the fifth interim analysis, the protocol was further amended to also include the CPRD 
Aurum database and to extend the study period to the end of 2021 for both CPRD 
databases.

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BI Study Number 1245.97 
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Proprietary confidential information © 2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of the finished medicinal 
product:
Jardiance®, Synjardy
Name of active ingredient:
Empagliflozin (A10BK03)
Metformin and empagliflozin (A10BD20)
Protocol date:
Study number/ 
Document number:
Version/Revision:
Version/Revision date:
16-Sep-2015
1245.97 / c03856813-10
8.0
17-May-2023
Data analysis:
For the primary, secondary, and further objectives, the main data analysis will be 
conducted in two stages: (i) construction of the PS-matched cohort by modelling the 
exposure to empagliflozin vs. DPP-4 inhibitors and (ii) estimating the effect of 
exposure to empagliflozin on the urinary tract (bladder, renal and other) cancers using 
aHR compared to those exposed to DPP-4 inhibitor and their respective IRs. Additional 
sensitivity analyses will be performed to validate the robustness of alternative 
definitions of outcome, exposure, and covariates, to assess reduction of bias due to 
matching and presence of detection/diagnostic bias, and to evaluate the current use of 
empagliflozin exposure using an AT analysis. Patients starting a combination of 
empagliflozin, and metformin (whether a fixed-dose or free combination) will be 
compared with patients starting a combination of a DPP-4 inhibitor and metformin. 
Depending on sample size, combination exposures with metformin will be accounted 
for through separate PS, stratification, or adjustment.
IRs (crude and adjusted) will be presented for each exposure group and stratified by 
relevant variables using the Poisson regression approach. Relative risks will be 
presented as hazard ratios (HRs) adjusted for relevant variables using the Cox’s model 
with the time- varying covariate approach. The aHRs and IRs will be presented along 
with 95% CIs for the risk estimates. Country-level estimates will be entered into meta-
analysis models to compute pooled estimates.

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BI Study Number 1245.97 
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Proprietary confidential information © 2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of the finished medicinal 
product:
Jardiance®, Synjardy
Name of active ingredient:
Empagliflozin (A10BK03)
Metformin and empagliflozin (A10BD20)
Protocol date:
Study number/ 
Document number:
Version/Revision:
Version/Revision date:
16-Sep-2015
1245.97 / c03856813-10
8.0
17-May-2023
Milestones:
Jardiance (empagliflozin) was granted EU marketing authorisation in May 2014. 
Launch in the UK and Finland was in August 2014; launch in Sweden took place 
November 2014. Synjardy (empagliflozin/metformin hydrochloride) was granted EU 
marketing authorisation in May 2015. Protocol version 1 was submitted to the EMA 
for review in September 2015, version 2 in February 2016, version 3 in June 2016, 
version 4 in March 2019, and protocol version 5.0 in Sep 2019. Registration in the EU 
PAS register occurred in December 2016 (EUPAS16424) and was updated following 
protocol endorsement by the EMA. The number of users in each treatment cohort have 
been monitored. Based on the available patient numbers and the event rates observed, 
a decision will be made to proceed with adjusted, treatment-stratified analyses at the 
interim report stage. Any decision based on the results of the interim reports concerning 
the length of the study period or the use of other data sources will be approved via a 
protocol amendment. Taking into account the database lags, the analysis of Swedish 
and Finnish data through December 2020 will be performed between Q3 2022 and Q3 
2023. Analysis of CPRD data through December 2021 will be performed in Q3/Q4 
2023 and the final report will be finalised by Q2 2024. Progress reports including 
monitoring of users in each data source were sent to EMA annually up to 2021.

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4.
AMENDMENTS AND UPDATES
Amendment 
number
Date
Section of 
study 
protocol
Amendment or 
update
Reason
8.0
17 May 
2023
5
Update of planned 
date for final study 
report
Delayed CPRD 
approval of study 
collaborators agreement
7.0
28 June 
2022
Multiple
To include data 
from the Clinical 
Practice Research 
Datalink (CPRD) 
Aurum database in 
the study.
European Medicines 
Agency (EMA)
requested to reconsider 
the inclusion of CPRD 
Aurum as an additional 
study database in the 
UK to capture as many
CPRD UK patients as 
possible, increase the 
sample size, and 
improve the study 
power in this country.
Multiple
Study period 
extended until 31st
December 2021, for 
the CPRD (GOLD 
and Aurum).
To increase the sample 
size, and improve study 
power in the UK.
Multiple
To not include data 
from the Cancer 
registry from the 
United Kingdom 
(UK) in the study.
Data linkage for a 
sensitivity analysis 
(Section 8.7.2.3) is not 
available in time for the 
final report submission. 
Multiple
To update the 
power calculations.
EMA requested to 
update the power 
calculations for the UK,
taking into account the 
inclusion of CPRD
Aurum as additional 
country-specific data 
source, and for Finland,
taking into account that 
1:2 matching ratio may 
be feasible in this 
country.

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Amendment 
number
Date
Section of 
study 
protocol
Amendment or 
update
Reason
8.7.1.4
To briefly describe 
the appropriate 
statistical methods.
EMA requested to
briefly describe the 
appropriate methods to 
combine results 
obtained from the main 
analysis performed in 
the different data 
sources, including the 
meta-analytical 
techniques such as the 
meta-analysis model 
and analysis and 
handling of 
heterogeneity or 
describe the process to 
identify the most 
appropriate method.
6.0
26 
January
2022
Multiple
To not include data 
from the Clinical 
Practice Research 
Datalink (CPRD) 
Aurum database in 
the study.
The study will have 
adequate power to 
demonstrate a 
significant difference 
assuming the target 
hazard ratios with 
patients from the data 
sources mentioned in 
the study (i.e., national 
registers in Sweden and 
Finland and CPRD 
GOLD database). 
Therefore, additional 
data from the Aurum 
database is not needed. 

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Amendment 
number
Date
Section of 
study 
protocol
Amendment or 
update
Reason
Information on Aurum 
database was removed 
from this protocol. 
Multiple
To use the highest 
possible matching 
ratio between 
initiators of 
empagliflozin and 
(dipeptidyl 
peptidase-4) DPP-4 
inhibitors. 
It was observed in the 
last interim report that 
there were not enough 
patients for 1:3 
matching in Finland and 
Sweden. Therefore, 1:1 
or highest possible 
matching ratio will be 
used in each country.
Multiple
To remove sodium 
glucose co-
transporter-2 
(SGLT-2) 
inhibitors as a 
comparison group 
from the study 
analyses.
It was observed in the 
last interim report that 
the yearly number of 
patients initiating 
SGLT-2 inhibitors other 
than empagliflozin 
decreased during the 
study period (2014-
2020). The total number 
of SGLT-2 inhibitors 
was considerably lower 
than that of 
empagliflozin initiators 
(a 1:1 matching cannot 
be performed), 
therefore only patients 
initiating DPP-4 
inhibitors will be used 
as a primary 
comparison group.

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Amendment 
number
Date
Section of 
study 
protocol
Amendment or 
update
Reason
8.7
Meta-Analysis
Data from Finland and 
Sweden cannot be 
transferred out of the 
country of origin. 
Therefore, pooling of 
all data and pooled 
analyses cannot be 
conducted. Information 
on pooled analyses was 
removed and instead 
meta-analysis was 
added to the protocol 
where relevant.  
8.4.3
Findata
In Finland, all the data 
will be delivered to and 
analyzed in the remote 
access server 
environment provided 
by the national permit 
authority Findata. The 
data holders will extract 
the relevant data and 
deliver it to Findata for 
pseudonymization.
Multiple
Other minor 
updates.
To align updates 
holistically.
5.0
23 
August 
2019 
Multiple
Inclusion of new 
study country, 
Finland.
To increase of the size 
of the patient 
population.
Multiple
Using DPP-4 
inhibitors as the 
primary 
comparison group 
and other SGLT-2 
inhibitors as the 
secondary 
comparison group.
Comparison with other 
SGLT-2 inhibitors is 
expected to be 
underpowered due to 
the low uptake of 
SGLT-2 inhibitors other 
than empagliflozin.
Multiple
Extending the study Increasing the study 

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Amendment 
number
Date
Section of 
study 
protocol
Amendment or 
update
Reason
period until 31st
December 2020.
sample size and 
accounting for the long 
latency period related to 
risk of malignancies.
9.5
Updated power 
calculations.
The power calculations 
have been updated as a 
result of extending the 
study period.
9.4.4
Additional 
information on 
potential data 
sources included.
Additional data sources 
can be included if the 
study size will be too 
small with the current 
data sources.
Multiple
Details provided on 
how fixed-dose 
combination drugs 
are processed in the 
study.
Several fixed-dose 
combination drugs have 
become available after 
the previous protocol 
version was approved. 

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5.
MILESTONES
Milestone
Planned Date
Actual date
Protocol endorsed by the 
European Medicines Agency 
(EMA)
Q3 2016
19 Sept 2016
Start of data collection
Expected during Q3 2016, 
depending on final protocol 
approval by the EMA
21 Oct 2016
Interim report 24 months
Q1 2017
Will be based on Swedish and 
the UK data available 24 
months after use of 
empagliflozin is first captured 
(November 2016)
13 Mar 2017
Interim report 36 months
Q1 2018
Will be based on Swedish and 
the UK data available 36 
months after use of 
empagliflozin is first captured 
(November 2017)
02 Apr 2018
Interim report 48 months
Q1 2019
Will be based on Swedish and
the UK data available 48 
months after use of 
empagliflozin is first captured 
(November 2018). 
19 Mar 2019
Interim report 60 months
Q1 2020
Will be based on Swedish, the 
UK and Finnish data available 
60 months after use of 
empagliflozin is first captured 
(November 2019)
13 May 2020
Interim report 72 months
Q1 2021
Will be based on Swedish, the 
UK, and Finnish data available 
72 months after use of 
empagliflozin is first captured 
(November 2020)
23 June 2021

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Milestone
Planned Date
Actual date
End of data collection
Q4 2021
Taking into account the 
database lags, analysis of 
Swedish and Finnish data 
through December 2020 will be 
performed between Q3 2022 
and Q3 2023. Analysis of 
CPRD data through December 
2021 will be performed in 
Q3/Q4 2023.
-
Registration in the EU PAS 
register1
Q4 2016 
30 Nov 2016
Final report of study results
Q2 2024
-
Registration of study results 
in the EU PAS register
Three months following 
approval of final study report
-
Note: Approvals by data protection, data custodian, ethics, and scientific review bodies are pending. Timelines may be 
impacted by approvals of these bodies, duration of contract reviews, and availability of data and staff at research 
institutions once contracts and approvals are finalised.
Sponsor to submit to EMA the results of the interim and final study reports within the earliest corresponding PSURs.
1 Website for the EU PAS Register: encepp.eu/encepp_studies/indexRegister.shtml.

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6.
RATIONALE AND BACKGROUND
Jardiance (empagliflozin), a highly potent and selective inhibitor of the sodium glucose co-
transporter 2 (SGLT-2), was approved in Europe in May 2014 for the treatment of type 2 
diabetes (T2D) to improve glycaemic control in adults. Synjardy (empagliflozin/metformin 
hydrochloride) was approved in Europe in May 2015. SGLT-2 is highly expressed in the 
kidney; as the predominant glucose transporter, it is responsible for the reabsorption of 
glucose from the glomerular filtrate back into the circulation. Empagliflozin improves 
glycaemic control in patients with T2D by reducing renal glucose reabsorption [R14-4617].
The recommended starting dose is 10 mg empagliflozin once daily. In patients tolerating 
empagliflozin 10 mg once daily who have an estimated glomerular filtration rate (eGFR) ≥ 60 
mL/min/1.73 m2 and need tighter glycaemic control, the dose can be increased to 25 mg once 
daily. The maximum daily dose is 25 mg [R14-4617].
In Europe, empagliflozin/metformin hydrochloride is available in the following fixed-dose 
combinations:

5 mg empagliflozin plus 850 mg or 1000 mg metformin hydrochloride

12.5 mg empagliflozin plus 850 mg or 1000 mg metformin hydrochloride
The recommended dose for the fixed-dose combinations is one tablet twice a day [R17-0153].
Currently, little information is available on whether there is a potential increased risk of 
cancers of the urinary tract associated with empagliflozin use. Clinical data with 
empagliflozin has not identified or established a potential mechanism for the development of 
malignancies. However, “urinary tract malignancies” are listed in the Risk Management Plan 
(RMP) as a potential risk. The inclusion of renal cancer as a potential risk was based on 
preclinical toxicology findings and clinical cases of bladder cancer observed with other 
SGLT-2 inhibitors.
As a part of the RMPs for empagliflozin and empagliflozin/metformin hydrochloride agreed 
upon by the European Medicines Agency (EMA), a post-authorisation safety study (PASS) 
will be performed to assess the risk of urinary tract malignancies in incident users of
empagliflozin, compared to incident users of dipeptidyl peptidase-4 (DPP-4) inhibitors, 
which is an alternative treatment option to empagliflozin and is prescribed at a similar 
diabetes progression stage. Prior to the development of the first version of the protocol for 
this study, a feasibility assessment of three databases in Europe (the CPRD [GOLD and 
Aurum] and data with potential for linkage (HES and ONS mortality statistics) in the United 
Kingdom (UK) and the national registers in Sweden and Finland) was performed with the 
aim to detail the minimum data requirements for the study and to assess, for each potential 
data source, the data quality, completeness of recorded information for urinary tract 
malignancies, and possibility of linkage with cancer registries, mortality registries and other 
data sources. The first version of the protocol included two study countries: Sweden and the 
UK. with follow-up until 31st December 2019. In version 6.0 of the protocol, the study 
follow-up was extended until  31st December, 2020 and Finland national registers were 
included to increase both accumulated patient-years and the number of patients initiating the 
study drugs. 

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In this version of the protocol (Version 7.0), additional steps were taken to increase sample 
size and follow-up for the UK. CPRD Aurum was added as an additional database to be 
pooled with CPRD-GOLD and the study period for both CPRD databases was extended to
31st December, 2021.
6.1
EPIDEMIOLOGY OF URINARY TRACT MALIGNANCIES IN 
DIABETES PATIENTS
Based on data from the national cancer registries throughout the Nordic countries, the crude 
incidence rates (IRs) for urinary tract malignancies (bladder and renal cancers) in the Nordic 
countries in 2013 was calculated as 43.0 per 100,000 person-years (PY) for the total 
population and 82.8 per 100,000 PY for individuals over 40 years of age (Table 1) [R15-
4873]. As the study population consists of T2D patients who initiate second- or third-line 
treatment, the majority of the patients are expected to be over 40 years old. The crude 
incidences of bladder cancer in the UK, as reported through cancer registries to 
GLOBOCAN, were lower, as compared to the Nordic countries, but rates for renal cancer 
were comparable (Table 1) [R15-4860]. In both regions, incidences are higher among men.
Table 1
Crude incidence rates per 100,000 person-years for urinary tract 
cancers, Nordic countries 2013 and the UK 2012 
Nordic Countries
The UK
Male
Female
Total
Male
Female
Total
Total Population
Bladder
43.7
14.6
29.1
20.5
7.6
14
Renal
17.6
10.2
13.9
19.6
11.5
15.5
UT (bladder + renal)
61.3
24.9
43.0
40.1
19.1
29.5
Age ≥ 40 years
Bladder
87.3
27.7
56.5
47.2
16.5
31.2
Renal
34.3
18.8
26.3
44.0
23.9
33.5
UT (bladder + renal)
121.6
46.5
82.8
91.3
40.4
64.7
Source: R15-4873; R15-4860
UK=The United Kingdom; UT=Urinary tract
T2D seems to be associated with an increased risk of several types of cancer when compared 
to the general population. Reviews of recent studies and meta-analyses indicate increased 
risks for liver, pancreas, colorectal, kidney, bladder, endometrial and breast cancers, as well 
as non-Hodgkin’s lymphoma in patients with T2D [R10-6494, R12-2439, R12-0469]. A
population-based cohort study on patients hospitalized with T2D diagnoses in Denmark 
showed a higher risk of kidney cancers (with the standardized incidence ratios (SIRs) of 1.4 
(95% confidence interval (CI); 1.2–1.6) in males and 1.7 (95% CI; 1.4–1.9) in females) and 
liver cancers (with the SIRs of 4.0 (95% CI; 3.5–4.6) in males and 2.1 (95% CI; 1.6–2.7) in

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females) associated with T2D, but not a higher risk for bladder cancer [R15-4869]. Another 
Swedish inpatient register-based cohort indicated a higher risk of kidney cancer associated 
with T2D in both women (SIR = 1.7, 95% CI; 1.4-2.0) and men (SIR = 1.3; 95% CI; 1.1-1.6) 
throughout the duration of follow-up (1-25 years) [R10-6630]. Crude IRs of bladder cancer in 
patients with T2D range from 38 per 100,000 PY in women from Denmark [R12-1334] to 
140-150 per 100,000 PY in men in Sweden and Denmark [R12-0368, R12-1334]. Meta-
analyses of observational studies suggest that incidence of kidney cancer in patients with 
T2D is approximately 40% higher than that in the general population [R13-1812]. The 
available crude incidence estimates of renal cancer in men with T2D range between 40 and 
50 per 100,000 PY in most studies.
Co-existence of hyperinsulinemia and hyperglycaemia in T2D and associated obesity may 
have a higher associated risk for cancers [R10-6494]. However, there may be additional risks 
from antidiabetic treatments and insulins, albeit these may be non-significant risks [R10-
6494]. Other risk factors of urinary tract cancer are smoking amount and duration ]R15-
4868], different occupational and environmental exposures [R15-4865], history of 
kidney/ureter stones [R15-4863], sex, chronic bladder irritation and infections, genetics and 
family history, chemotherapy and radiation therapy [R15-4866; R15-4856].
6.1.1
Incidence of urinary tract malignancies in the study population in the UK 
and Sweden observed in the fifth interim report of this study 
The country-specific IRs of urinary tract malignancies were estimated in the study population 
identified in the UK, Sweden and Finland, from 1st August 2014 to 31st December 2020 
(2019 for Sweden).
In the UK CPRD GOLD, during a total of 147,020 patient years, 164 urinary tract cancer 
events were recorded in the study population with an incidence rate of 111.5 (95% CI, 95.7-
130.0) per 100,000 patient years. The incidence rate of bladder cancer was 66.7 (95% CI, 
54.7-81.2) per 100,000 patient years with a total of 98 events. For renal cancer, the incidence 
rate was 26.5 (95% CI, 19.4-36.3) per 100,000 patient years with a total of 39 events. 
In Sweden, during a total of 210,329 patient years, 346 urinary tract cancer events were 
recorded in the study population with an incidence rate of 164.5 (95% CI, 148.1-182.8) per 
100,000 patient years. The incidence rate of bladder cancer was 104.1 (95% CI, 91.2-118.9) 
per 100,000 patient years with a total of 219 events. For renal cancer, the incidence rate was 
58.0 (95% CI, 48.6-69.3) per 100,000 patient years with a total of 122 events. 
In Finland, during a total of 256,947 patient years, 415 urinary tract cancer events were 
recorded in the study population with an incidence rate of 161.5 (95% CI, 146.7-177.8) per 
100,000 patient years. The incidence rate of bladder cancer was 86.8 (95% CI, 76.1-99.0) per 
100,000 patient years with a total of 223 events. For renal cancer, the incidence rate was 71.6
(95% CI, 62.0-82.7) per 100,000 patient years with a total of 184 events. 

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6.2
EPIDEMIOLOGY OF DIABETES AND DIABETES TREATMENT 
PATTERNS IN THE UK
The prevalence of diabetes has increased in the UK from 2.8% in 1996 to 4.3% in 2005, and 
the incidence has increased from 2.7 per 1,000 PY in 1996 to 4.4 per 1,000 PY in 2005. 
During the period 1996-2005, a change in oral glucose lowering medication use has occurred,
predominantly from sulfonylureas to metformin [R11-5320]. Moreover, since 2005-2006, the 
use of thiazolidinediones has decreased due to concerns about cardiovascular safety, which 
led to suspension of the rosiglitazone marketing authorisation in the European Union in 2010 
[R12-1620]. Together with the introduction in the market of DPP-4 inhibitors, this has 
changed the selection of second-line treatment regimens, as shown in two studies performed 
in the UK. One was a cohort study performed in the CPRD from 2000 to 2010, which found 
that the combination of metformin and DPP-4-inhibitors represented 0.7% of all second-line 
regimens in 2007, but DPP-4 inhibitors were prescribed in 20.2% of all second-line regimens 
in 2010 [R14-5249]. On the other hand, the combination of metformin and thiazolidinediones 
(pioglitazone or rosiglitazone) represented 34% of the all second-line regimens in 2007 but 
only 9.8% in 2010 [R14-5249]. The other study was performed in The Health Improvement 
Network (THIN) database, where the annual incidence of prescriptions of thiazolidinediones 
decreased from 1.2 per 1,000 PY in 2007 to 0.8 per 1,000 PY in 2009, at the same time that 
“other glucose lowering drugs,” including DPP-4 inhibitors, increased from 0.2 per 1,000 PY
to 1.1 per 1,000 PY [R14-5244].
As part of the feasibility assessment, patient counts for users of empagliflozin and other 
glucose lowering medications were extracted from CPRD GOLD database in the UK for the 
period January 2014 through May 2015 (Table 2). During this time, metformin was the most 
frequently used glucose lowering medication followed by sulphonylureas, and DPP-4 
inhibitors; utilization of empagliflozin was still low.
Table 2
Patient counts by Glucose Lowering Medication category in the
UK, Sweden, and Finland
Drug category
The UK1
Sweden2
Finland3
Biguanides
149,987
235,342
246,444
Sulphonylureas
64,006
35,890
9,381
Combinations
2,654
2,552
39,937
Alpha glucosidase inhibitors
424
703
None
Thiazolidinediones
9,849
1,535
4,565
DPP-4 inhibitors
30,918
13,430
94,722
Empagliflozin
108
373
24,968
Others, excl. insulins
9,088
15,151
1,867
1 Data from CPRD GOLD, January 2014- July 2015 (end date varies slightly by GP practice). 2 2014. 3 2017

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6.3
EPIDEMIOLOGY OF DIABETES AND DIABETES TREATMENT 
PATTERNS IN SWEDEN AND FINLAND
The total age-standardized prevalence of both pharmacologically and non-pharmacologically 
treated diabetes was 4.69% in 2012 in Sweden. The age-standardized prevalence of 
pharmacologically treated diabetes increased from 4.19% and 2.99% in 2005/2006 to 5.08% 
and 3.46% in 2012/2013 in men and women, respectively [R15-4858]. In Finland, 4.3% of 
women and 7.4% of men aged 45-74 years are diagnosed with diabetes [P19-01624]. In 2016, 
5.7% of the Finnish population were dispensed a diabetes drug with a special reimbursement 
for the costs.
As part of the feasibility assessment, patient counts for users of empagliflozin and other 
glucose lowering medications were extracted from the Prescribed Drug Register in Sweden 
for 2014 (Table 2). During this time, metformin was, by far, the most frequently used glucose 
lowering medication, followed by sulphonylureas and DPP-4 inhibitors; utilization of 
empagliflozin was still low.
More recent numbers in Finland indicate that metformin was the most frequently used 
glucose lowering medication in 2016 (Table 2). Empagliflozin use has had a major increase: 
the number of patients in Finland has increased from 1,007 in 2015 to 24,968 in 2017 [P19-
01956].
6.4
RISK OF BLADDER CANCER IN PREVIOUS TRIALS OF SGLT-2 
INHIBITORS
In a clinical trial comparing empagliflozin with placebo, three (0.1%) and nine (0.4%) cases 
of bladder cancer were observed in persons exposed to 10 mg and 25 mg empagliflozin, 
respectively, while five cases (0.2%) were observed among those with exposure to placebo 
[P19-01957]. Further, dapagliflozin and canagliflozin, in comparison to placebo, did not 
increase the risk of bladder cancer in clinical trials [R19-2814, P19-07186]. The hazard ratios
(HRs) for dapagliflozin, and canagliflozin were 0.57 (95% CI 0.35-0.93) and 0.90 (95% CI 
0.47-1.72), respectively. Therefore, contrary to the preclinical toxicology findings, SGLT-2 
inhibitors did not show an increased risk of bladder cancer in clinical trials.
6.5
RATIONALE FOR THE PROTOCOL AMENDMENT
1. The CPRD Aurum database is added to the study data sources. EMA requested to 
reconsider the inclusion of CPRD Aurum as an additional study database in the UK to 
capture as many CPRD UK patients as possible, increase the sample size, and 
improve the study power in this country and in the study overall.
2. The study period is extended until 31st December, 2021, for CPRD databases (GOLD 
and Aurum). To increase the sample size and improve study power in the UK, the 
study period is extended to 31st December, 2021, for the CPRD databases.
3. Data from the Cancer registry from the United Kingdom (UK) is not included in the 
study. Data linkage for a sensitivity analysis (Section 8.7.2.3) is not available in time 
for the final report submission. 

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4. Power calculations are updated using assumptions made from the data available in the 
5th Interim Report (2021). EMA requested to update the power calculations for the 
UK considering (1) the inclusion of CPRD Aurum as additional country-specific data 
source, and (2) using a 1:2 matching ratio for Finland as this matching ratio should be 
feasible in this country whilst 1:3 will not.
5. Additional details regarding the meta-analysis method are included. EMA requested 
to briefly describe the appropriate methods to combine results obtained from the main 
analysis performed in the different data sources. This includes describing the meta-
analytical techniques such as the meta-analysis model and analysis, describing the
handling of heterogeneity, and/or describe the process to identify the most appropriate 
method for running the meta-analysis.

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7.
RESEARCH QUESTION AND OBJECTIVES
Research Question
The aim of the study is to assess the risk of urinary tract malignancies in patients initiating 
empagliflozin compared to patients initiating a DPP-4 inhibitor.
Objectives:
Primary objectives:
I.
To estimate the adjusted hazard ratios (aHRs) and incidence rates (IRs) of all urinary 
tract cancers (bladder, renal and other urinary tract cancers) in patients initiating 
empagliflozin compared to patients initiating a DPP-4 inhibitor
II.
To estimate the aHRs and IRs of bladder cancer in patients initiating empagliflozin
compared to patients initiating a DPP-4 inhibitor
III.
To estimate the aHRs and IRs of renal cancer in patients initiating empagliflozin
compared to patients initiating a DPP-4 inhibitor
Secondary objective:
To estimate the aHRs and IR of each primary outcome (all urinary tract cancers, bladder 
cancer, renal cancer) with respect to:
a) increasing cumulative dosage of empagliflozin
b) dosage of empagliflozin prescribed per use (10mg vs 25mg)
c) time since first dose of empagliflozin

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8.
RESEARCH METHODS
8.1
STUDY DESIGN
This is a non-interventional, comparative, cohort safety study based on European healthcare 
databases and includes databases from the UK, Sweden and Finland. 
The study will use an “incident users” design and compare new users of empagliflozin to new 
users of DPP-4 inhibitors. The index date will be defined as the date on which each identified 
new user receives the index prescription for empagliflozin, or a DPP-4 inhibitor. The 
incident-user design avoids comparing a population predominantly composed of first-time 
users of a newly marketed drug such as empagliflozin with a population of prevalent users of 
an older drug who may have stayed on the comparator treatment for a longer time and be less 
susceptible to the events of interest. To avoid the inclusion of prevalent users, patients will be 
required to have no exposure to empagliflozin or a DPP-4 inhibitor during the available look-
back (pre-index) period [R13-1120, R14-4378].
DPP-4 inhibitors have been selected as the comparator group for several reasons. First, the 
National Institute for Health and Care Excellence (NICE) appraisal of dapagliflozin (an 
SGLT-2 inhibitor) recommended that dapagliflozin should be used as described for DPP-4 
inhibitors. The NICE Evidence Review Group considered that, overall, “DPP-4 inhibitors are 
the key comparators for dapagliflozin in both the dual therapy and triple therapy settings” 
[R13-5134]. Second, DPP-4 inhibitors, SGLT-2 inhibitors, and thiazolidinediones have 
similar indications and target population, while dual therapy with GLP-1 (glucagon-like 
peptide-1) analogues has a restricted target population [P14-17374] and metformin and 
sulfonylureas are typically used earlier in the treatment paradigm. Finally, the use of 
thiazolidinediones has decreased in recent years, given increasing concerns about their safety 
(including bladder cancer), and at the same time, use of DPP-4 inhibitors increased, making 
second-line regimens with DPP-4 inhibitors the most common second-line regimens after 
metformin with sulfonylurea [R14-5244, R14-5249].
Empagliflozin is usually a second- or third-line treatment for T2D; thus, it is expected that 
few patients with T2D initiating empagliflozin will be treatment naïve. For the majority of 
patients, empagliflozin will be added to an existing treatment (e.g., added to metformin), or 
patients will be switched to empagliflozin (e.g., from metformin plus an oral glucose 
lowering medication other than the study drugs to metformin plus empagliflozin) due to 
disease progression, treatment failure, or side effects that may be related to study outcome. 
Analyses will account for treatment complexity (monotherapy, dual combination therapy, or
triple combination therapy) to achieve a fair comparison between groups [R13-1120, 
R14-4378] and concomitant use of metformin (whether a fixed-dose or free combination). 
Despite the selection of comparators with similar utilization patterns to empagliflozin, the 
cohorts created with incident users of DPP-4 inhibitor drug group may have inherent 
channelling bias wherein the treatment assignment is influenced by a range of factors such as 
disease progression, comorbidity, treatment history, age, and sex. Additionally, some of these 
variables lead to increased or decreased risk of cancer. To minimize channelling bias, 
individuals are matched with similar treatment and clinical history at index date by deriving 

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propensity scores (PS) conditional on factors affecting the treatment and outcome [R13-1120, 
R14-4378]. Propensity-score-matched cohorts will be derived from the study base by 
matching patients who initiate empagliflozin with patients who initiate DPP-4 inhibitors at 
index date with the highest possible matching ratio (1:1, 1:2, or 1:3 using Greedy matching 
methods). Depending on sample size, combination exposures with metformin will be 
accounted for through separate PS, stratification, or adjustment. Additional analyses will 
explore the presence of detection/diagnostic bias as screening for urinary tract signs or 
symptoms may be more frequently among empagliflozin users. The potential for diagnostic 
bias will be evaluated and addressed through consideration of the frequency of urine dipstick 
testing (as captured through albuminuria tests) and stage of cancer at the time of diagnosis (as 
more early-stage cancers in one group would be suggestive of diagnostic bias).
The primary, secondary, and further analyses utilize a cohort design which will allow direct 
estimation of the IRs and aHRs of multiple outcomes of interest among new users of 
empagliflozin compared with new users of a DPP-4 inhibitor. The covariate information will 
be assessed during the time preceding treatment initiation (varying length look-back (pre-
index) period) and during follow-up and will include all historical information available for 
each patient up until occurrence of outcome or censoring (see Section 8.3.3). Follow-up will 
start 6 months after the index date (12 months in sensitivity analyses) to account for an 
empirical induction/promotion period (see Section 8.3.5). In the context of data sources such 
as the CPRD and the Swedish and Finnish national registers, the use of a cohort design has 
more advantages than limitations compared with the use of a nested case-control (NCC) 
design—see the appendix discussion in Schneeweiss (2010) [R13-1120] and Patorno et al. 
(2014) [R14-4378]. Thus, an observational cohort is constructed to study the risk of urinary 
The country-level datasets will be analysed separately. Country-level effect size estimates 
(IRs, aHRs, etc) will be pooled using suitable meta-analysis methods to compute overall
estimates.
8.2
SETTING
8.2.1
Study populations
The source population will include all patients with T2D from the UK, Sweden, and Finland. 
In the UK, the population will include patients with T2D from the CPRD databases of 
longitudinal medical records collected from the UK primary care practices (CPRD GOLD
and CPRD Aurum). Sensitivity analyses may include a subset of the CPRD GOLD and 
CPRD Aurum database eligible for linkage to Hospital Episode Statistics (HES) data and/or
to Office of National Statistics (ONS) mortality data if linked data with sufficient sample size 
during the study period are available (see Section 8.4.1). In Sweden and in Finland, patients 
with T2D in the nationwide registers will be included. All patients with T2D who have 
purchased at least one prescription of empagliflozin, or a DPP-4 inhibitor during the study 

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period (2014-2021 for CPRD GOLD and Aurum, 2014-2021 for Sweden and Finland) will be 
included in the study. Identification of diabetes will be based on medical/prescription records 
and all non-T2D patients will be excluded.
8.2.2
Study period
The study will include individuals who have purchased at least one prescription of 
empagliflozin, or DPP-4 inhibitors, from 1st August 2014 through 31st December 2020 (31st 
December 2021 for CPRD). The starting of the study period corresponds to the time of drug 
licensing (second half of 2014 in all three countries) and subsequent introduction into clinical 
practice. The number of users in each treatment cohort will be monitored at 24 months after 
empagliflozin use starts being captured in the data sources (November 2016) and annually 
thereafter until 2021. The maximum follow-up time for an individual will be seven years for 
CPRD GOLD and Aurum and 6 years for Sweden and Finland.
8.2.3
Index date
The index date will be defined as the date of first purchase/prescription of empagliflozin, or a 
DPP-4 inhibitor, during the study period (2014-2020).
8.2.4
Baseline and look-back (pre-index) period
To characterise the empagliflozin, or DPP-4 inhibitor cohorts at the time of study drug 
initiation, all information available during the look-back (pre-index) time period will be 
collected. The look-back time period is defined as the time period ending on the day before 
the index date. Since all cohort members are required by inclusion criteria to have at least 1 
year of data before the index date (baseline period), the look-back period will include at least 
365 days during which covariates can be evaluated. For some study participants, data on 
covariates might be available beyond 1 year prior to the index date; in these cases, all 
available information will be considered for covariate classification related to diabetes, 
diabetes medications, and concomitant chronic conditions. For concomitant medications for 
diseases other than diabetes, the look-back time period will be limited to 180 days prior to the 
index date. 
If the distribution of the duration of look-back time period is different among empagliflozin, 
or DPP-4 inhibitor categories of look-back time will be created using indicator variables. 
Those indicator variables will then be used as covariates in the multivariable regression 
models for outcome prediction, and for PS development, to control for possible differences in 
availability of information between the empagliflozin and comparator cohorts.
8.2.5
Inclusion and exclusion criteria
The study population will be selected from the broad study population with the following 
inclusion and exclusion criteria:
Inclusion criteria:

Diagnosis of T2D

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o
To identify the diagnosis in the UK, lists of codes that have been previously 
used to identify patients with T2D in the CPRD [P14-16383] will be utilized 
(Annex 3).
o
For Swedish registers, identification of diabetes will be based on prescription 
records and the National Diabetes Register; all non-T2D patients will be 
excluded. The final algorithm to identify patients with T2D in each data 
source, which might include medication codes and glucose/glycated 
haemoglobin test results, will be described in the statistical/epidemiological 
analysis plan (SEAP).
o
In Finnish registers, identification of patients with T2D will be based on 
prescription records and diagnoses available in various data sources; all non-
T2D patients will be excluded. More specifically, all persons with 
dispensations of empagliflozin, or a DPP-4 inhibitor will be identified. 
Patients with non-T2D will be identified with the following criteria: special 
reimbursement of diabetes drugs with an ICD-10 diagnosis for a non-T2D, 
type 1 diabetes mellitus (T1D), pre-existing T1D before pregnancy, 
gestational diabetes, malnutrition-related to diabetes mellitus, neonatal 
diabetes mellitus, other specified diabetes mellitus, diabetes mellitus due to 
underlying condition, and drug- or chemical-induced diabetes mellitus. The 
specific diagnosis codes will be included in the SEAP.

Age over 18 years at index date.

At least 1 year of membership in the medication database prior to index date; in 
CPRD, at least 1 year of continuous up-to-standard registration in the CPRD prior to 
the index date.
o
This is the minimum look-back period and is informative of the history of 
treatments and other medical conditions in the recent past. Some of the 
important covariates to be accounted for in matching at index date are 
derived from the look-back period.
Exclusion criteria: 

Patients with any cancer (excluding non-melanoma skin cancer) recorded at any time 
prior to the index date (i.e., during the available look-back time).

Diagnosis of T1D or other specific non-T2D.

Use of any SGLT-2 inhibitor or any DPP-4 inhibitor (including free and fixed-dose 
combinations) recorded at any time prior to index date (i.e., during the available look-
back time). 

Use of fixed-dose combinations of SGLT-2 inhibitors with DPP-4 inhibitors.

Diagnosis of or procedures related to end stage renal disease, receipt of renal dialysis 
recorded, or eGFR ≤15 ml/min at any time prior to index date (i.e., during the 
available look-back time).
8.3
VARIABLES
The final list of variables and operational definitions will be presented in a separate SEAP to 
be developed prior to the start of data analysis. 

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8.3.1
Exposures
Empagliflozin (current ATC code A10BK03, previous ATC code A10BX12) is the exposure 
of interest, free or fixed-dose combination with metformin (ATC code: A10BD20).
The DPP-4 inhibitor comparator exposure group will consist of the following drugs, free or 
fixed-dose combination with metformin (See Section 8.1 and Annex 4). 

Alogliptin 

Linagliptin

Saxagliptin

Sitagliptin

Vildagliptin
If additional DPP-4 inhibitors are introduced in any of the study countries during the study 
period, they will also be considered to be members of the corresponding comparator group.
Note that use of any of these index drugs prior to index date is an exclusion criterion.
Information on whether patients received prior oral glucose lowering therapy or if they were 
“added on” or “switched to” empagliflozin, or a DPP-4 inhibitor at the time of inclusion in 
the study will be collected. Patients will be classified according to their treatment complexity 
as receiving monotherapy, dual combination therapy, or triple combination therapy and 
according to use of metformin combination therapy (fixed-dose or free combination). (See 
Section 8.1)
The primary definition of exposure, i.e., as-treated analysis (AT), is defined as an ongoing 
exposure (free or fixed-dose combination with drugs other than DPP-4 inhibitors and SGLT-2 
inhibitors) to one of the following two index drugs or drug groups: empagliflozin or DPP-4 
inhibitors (Table 3, Annex 4). Exposure is defined as use of these drugs during the study 
period starting from 6 months after the index date (see Sections 8.2.3 and 8.3.5)
As a typical prescription length is one month in the UK and three months in Sweden and 
Finland, multiple prescriptions are required for a patient to have continuous ongoing
treatment at 6 months after index date. Therefore, patients with only one prescription are 
unlikely to contribute to the AT analysis.
Secondary definitions of exposure include cumulative dosage of empagliflozin use, daily 
dosage of empagliflozin prescribed per use (10mg vs 25mg), and time since first dose of 
empagliflozin (Table 3, Annex 4).
Sensitivity analyses of exposure include intention-to-treat (ITT) analyses.

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Table 3
Exposure definitions for primary and secondary analyses
Exposure definition
Description
Time-dependent 
or Fixed at 
index date
Current exposure to 
study treatment (as-
treated analysis)
Indicator of current use of empagliflozin, or 
a DPP-4 inhibitor, either alone or as a 
combination.
Time-dependent
Exposure to 
Empagliflozin 
(Intention-to-treat)
Drug purchased/prescribed at index date,
which is one of empagliflozin, or a DPP-4 
inhibitor.
Fixed at index 
date 
Cumulative dosage of 
empagliflozin use
Time-dependent cumulative sum of drug 
consumption based on the daily defined 
dosage of empagliflozin since entry into the 
study cohort.
Time-dependent
Daily dosage of 
empagliflozin per use
The dosage of empagliflozin prescribed per 
daily use (10mg vs 25mg). 
Time-dependent 
Time since first dose of 
empagliflozin
Time-dependent cumulative sum of duration 
since the first use of (exposure to) 
empagliflozin.
Time-dependent
Treatment complexity
Monotherapy, dual combination therapy, or 
triple combination therapy (based on 
predefined groups).
Fixed at index 
date
Switch
Switch from the drug purchased/prescribed 
on index date to any other drug in the 
primary exposure.
Time-dependent
Concomitant use of 
insulin
Was empagliflozin an add-on to insulin 
(yes/no).
Fixed at index 
date
Concomitant use of 
metformin
Was empagliflozin an add-on to metformin 
(yes/no).
Fixed at index 
date
Concomitant use of 
metformin
Concomitant use of metformin either as 
fixed-dose combination or free 
combination.
Time-dependent
Ever used other oral 
glucose lowering 
medication
Use of other oral glucose lowering drugs 
based on predefined drug groups in the past.
Time-dependent
Ever used metformin
Was metformin ever used – taking value 
‘yes’ as soon as one prescription with 
metformin is purchased.
Time-dependent

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Exposure definition
Description
Time-dependent 
or Fixed at 
index date
Ever used sulfonylureas
Was sulphonylureas ever used – taking 
value ‘yes’ as soon as one prescription with 
sulphonylureas is purchased.
Time-dependent
Ever used 
thiazolidinediones
Was thiazolidinediones ever used – taking 
value ‘yes’ as soon as one prescription with 
thiazolidinediones is purchased.
Time-dependent
Ever used GLP-1
Was GLP-1 ever used – taking value ‘yes’ 
as soon as one prescription with GLP-1 is 
purchased.
Time-dependent
Ever used insulin
Was insulin ever used – taking value ‘yes’ 
as soon as one prescription with insulin is 
purchased.
Time-dependent
GLP=glucagon-like peptide
8.3.2
Outcomes
8.3.2.1
Primary outcomes
The outcomes of interest for this study are urinary tract cancers, bladder cancer, and renal 
cancer. These outcomes will be identified through CPRD GOLD and CPRD Aurum data and 
the national cancer registries in Sweden and Finland improving confidence in the accuracy 
and validity of these outcome diagnoses (See Section 8.4).
Date of diagnosis of the first incidence of urinary tract cancers as specified in CPRD GOLD
and CPRD Aurum, or in the Swedish or Finnish cancer registry after the entry into the study 
will be used as the primary outcome date. The urinary tract cancer definition will include 
malignant neoplasm and carcinoma in situ of the urinary tract. Only the first occurrence of a 
urinary tract cancer will be captured. Patients with a prior history of cancer, including a prior 
urinary tract cancer, will be excluded.
In the Swedish and Finnish datasets urinary tract cancer events will be identified from cancer 
registers using ICD-10 and ICD-O-3 codes (Annex 5). The reporting of all cancer cases is 
compulsory, and the completeness and quality of the register data are considered good for 
scientific research [R15-4864, R15-4867, R15-4857, R15-4871].
In CPRD, urinary tract cancer events will be identified in CPRD GOLD and CPRD Aurum 
using READ and SNOMED codes (Annex 5). A study evaluating the validity of cancer
diagnoses in CPRD compared with cancer registry data concluded that recording of cancer 
diagnoses in the two sources was generally consistent. The predictive value of a CPRD
GOLD diagnosis of urinary tract cancer was 92%. Taking all records of cancer in the general 

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practitioner (GP) data, 4% did not occur in the cancer registry data. Differences were 
generally due to different dates of diagnosis or tumour types [R15-4862].
Sensitivity analyses based on other outcome definitions as well as using a subset of  CPRD
GOLD and CPRD Aurum with linkage to HES data (Outpatient, HES OP; Admitted Patient 
Care, HES APC) data, will be performed to address some of the accuracy and validity issues 
in the primary outcomes (see Section 8.7.2).
8.3.3
Covariates
Variables potentially associated with urinary tract cancers, such as socio-demographic 
variables including age, sex, socioeconomic status, body mass index, smoking and alcohol 
consumption, laboratory measurements, concomitant medications, comorbidities, and 
duration of look-back period (see Section 6.1), will be identified for study participants as 
recorded prior to the index date (see Annex 6 for list of covariates to be included in the 
study). With the exception of exposure to toxic chemicals such as arsenic, known risk factors 
for urinary tract cancers are captured in CPRD and the national registers from Sweden and 
Finland.
Study participants will also be classified by indicator variables on the calendar time of cohort 
entry (by quarter) whether the index treatment (empagliflozin, or DPP-4 inhibitor) was added 
to existing medication (adding on), or if the index treatment was initiated as a replacement for 
another antihyperglycemic medication (switching to empagliflozin, or DPP 4 inhibitor), and 
whether this treatment was received as monotherapy or as dual or triple combination therapy. 
A variable indicating whether or not patients were receiving insulin at the index date will also 
be created.
The confounding due to covariates in this section are to be accounted for at minimum by 
design or analysis when estimating the risk of urinary tract cancers with the defined 
The examples of covariates in Table 4 describe the comorbidities, treatment history, and 
socio-demographic variables that will considered for inclusion. These variables along with 
times of occurrence/diagnosis of comorbidities, times of prescription/dispensing of drugs and
times of recording of the socio-demographic variables in combination with the exposure and 
outcome variables define the minimal required dataset.

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Table 4
Baseline covariates to be considered for inclusion alternatively 
or simultaneously in primary, secondary, and further analyses
Covariate
Exact 
matchin
g
PS 
matchin
g
Stratificatio
n
Database variable (for CPRD only)1
Patient database (Aurum 
vs GOLD)
Yes
Yes
Socio-demographic 
variables
Age
Yes
Yes
Yes
Sex
Yes
Yes
Yes
Socioeconomic status (if 
available)
Yes
Calendar year of index 
date
Yes
Duration of look-back 
period
Yes
Insulin concomitant (or 
cumulative duration of) 
use
Yes
Yes
Other oral 
antihyperglycemic
medication use
Yes
Comorbidities
Diabetic complications -
diabetic nephropathy-
diabetic neuropathy -
peripheral vascular 
diseases - lower limb 
severity
Yes
Yes
Yes
Urinary tract-related 
comorbidities
Yes
Yes
Yes
Kidney or genitourinary 
stones
Yes
Yes
Yes

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Covariate
Exact 
matchin
g
PS 
matchin
g
Stratificatio
n
Risk set 
(NCC) / 
covariat
e in 
MSM3
Model 
adjustmen
t4
Prior history of UTI or 
pyelonephritis
Yes
Yes
Yes
Liver disease
Yes
Yes
Yes
eGFR2
Yes
Yes
Yes
Renal impairment
Yes
Yes
Yes
Prior ICU admission
Yes
Yes
Yes
Pancreatitis
Yes
Yes
Yes
BMI (when available)
Yes
Yes
Yes
Smoking (when 
available)
Yes
Yes
Yes
Alcohol use (when 
available)
Yes
Yes
Yes
HbA1c (when available)
Yes
Yes
Yes
Albuminuria testing 
Yes
Yes
Yes
Cardiovascular Diseases 
(HF, Hypertension, 
stroke, MI)
Yes
Yes
Yes
Blood pressure 
measurements (when 
available)
Yes
Yes
Yes
Hypertension
Yes
Yes
Yes
Stroke
Yes
Yes
Yes
MI
Yes
Yes
Yes
Autoimmune disease
Yes
Yes
Yes
COPD
Yes
Yes
Yes
Time since first diabetes 
diagnosis
Yes
Yes
Yes
Other non-diabetes 
medications
Antihypertensives/diureti
Yes
Yes

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Covariate
Exact 
matchin
g
PS 
matchin
g
Stratificatio
n
Risk set 
(NCC) / 
covariat
e in 
MSM3
Model 
adjustmen
t4
cs
Non-steroidal anti-
inflammatory drugs 
(NSAIDs)
Yes
Yes
Oral steroids
Yes
Yes
Statins, fibrates
Yes
Yes
Lipid modifying agents
Yes
Yes
Zoledronic acid
Yes
Yes
Antibiotics
Yes
Yes
1 This variable will be present only for CPRD data. It will indicate which database (GOLD or Aurum) the patient data was 
extracted from-
2 Time-dependent eGFR estimate will be computed with the CKD-Epi equation from serum creatinine measurements, where 
available.
3 Sensitivity analyses
4 Covariates considered for inclusion if not balanced after PS matching
BMI=body mass index; COPD=chronic obstructive pulmonary disease; eGFR=estimated glomerular filtration rate; 
HbA1c=glycated haemoglobin A1c; HF=heart failure; ICU=intensive care unit; MI=myocardial infarction;
MSM=marginal structural model; NCC=nested case-control; PS=propensity score; UK CPRD=The United Kingdom 
Clinical Practice Research Datalink; UTI=urinary tract infection.
8.3.4
Censoring of follow-up time
The following events lead to censoring: all-cause mortality, emigration, patient transfer,
meeting specific exclusion criteria (see exclusion criteria in Section 8.2.5) and end of study 
period. Follow-up times will be censored at any of these events, whichever occurs first. In the 
primary AT analysis discontinuation of index drug treatment is an additional censoring 
variable. Treatment discontinuation is defined either by 

A switch from the index drug to any other drugs (empagliflozin, DPP-4 inhibitor, or 
other SGLT-2 inhibitor), or to a fixed-dose combination of a SGLT-2 inhibitor with a 
DPP-4 inhibitor (identified from the ATC class A10BD) plus a 3-month period 
following the switch, or

As the stop date plus a 3-month period following it. The stop date is the end date of 
the first continuous exposure period of the index drug, where continuous treatment is
defined as having consecutive prescriptions separated by 30 days or less (Figure 1).
The 3-month period after the switch or the stop date is used to allow for a delay in the 
diagnosis of cancer [R16-2539]. In a sensitivity analysis this time period is extended to 6 
months. 

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Switch to a fixed-dose combination including the same index drug and drugs other than DPP-
4 inhibitors and SGLT-2 inhibitors is not considered a censoring variable (for example, 
switch from sitagliptin to a fixed-dose combination including sitagliptin and pioglitazone).

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Figure 1
Discontinuation of index drug due to stopping of index drug or 
switching of index drug. In the primary analysis follow-up is censored 
at treatment discontinuation.
8.3.5
Follow-up time
For the primary AT analyses, the follow-up time (time at risk) will begin 6 months after the 
index date (lag period to account for empirical induction/promotion period of cancer) and end 
at urinary tract (bladder, renal or other) cancer or at any of the censoring events including 
discontinuation of index drug treatment.
For the sensitivity ITT analyses, the follow-up time will begin 6 months after the index date 
and end at urinary tract (bladder, renal or other) cancer or any of the censoring events
excluding treatment discontinuation of index drug.
Patients with censored follow-up time will not be able to re-enter study cohort at a later time 
point. Follow-up will not be censored if oral or injectable glucose lowering drugs other than 
the index drugs are prescribed in addition to empagliflozin, a DPP-4 inhibitor, or a SGLT-2 
inhibitor after the index date.
The lag period of 6 months is to account for an empirical induction/promotion period. 
Information in the first 6 months after the index date (i.e., first 6 months of follow-up) will be 
excluded, including patients with less than 6 months of follow-up and all occurrences of 
cancer within the first 6 months of follow-up, in order to consider a biologically meaningful 
induction/promotion time window. Sensitivity analyses will expand the lag period to 12 
months.

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8.4
DATA SOURCES
Prior to the development of the protocol for this study, a feasibility assessment of three 
databases in Europe (CPRD [GOLD and Aurum] and data with potential for linkage [HES
(Outpatient and Admitted Patient Care), and ONS mortality statistics] in the UK and the 
national registers in Sweden and Finland) was performed with the aim to detail the minimum 
data requirements for the study and to assess, for each potential data source, the data quality, 
completeness of recorded information for urinary tract malignancies, and possibility of 
linkage with cancer registries, mortality registries and other data sources. The minimal data 
requirements for data sources which were assessed are listed in Table 5. 

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Table 5
Minimum data requirements and data availability for the UK and the national registries in Sweden and 
Finland. 
x = available in the register, - = not available in the register
The UK
Sweden
Finland
CPRD 
(GOLD 
and 
Aurum) 
HES
Mortal
ity
Patient
Prescri
ption
Cancer
Cause 
of 
Diabet
es
HILM
O
AvoHI
LMO
Special 
Reimb
Prescip
tions
Cause 
of 
Cancer
s
EMR 
databa
Age
x
x
x
x
x
x
x
x
x
x
-
x
x
x
x
Sex
x
x
x
x
x
x
x
x
x
x
-
x
x
x
x
Medication
x
-
x3
x
-
-
x5
-
-
-
x
-
x
-
DDD
x
-
-
x
x
-
-
-
-
-
-
x
-
-
-
Purchase date
x1
-
-
x
x
-
-
-
-
-
-
x
-
-
-
Diagnoses
x
x
-
x4
-
x
-
x
x
x
x7
x9
-
x
-
Date of 
diagnosis
x
x
-
x
-
x
-
-
x
x
x8
-
-
x
-
Time of death
-
-
x
-
-
x
x
-
-
-
-
-
x
x
-
Cause of death
-
-
x
-
-
x
x
-
-
-
-
-
x
x
-
Smoking
x
-
-
-
-
-
-
x
x6
x6
-
-
-
-
x
BMI
x
-
-
-
-
-
-
x
x6
x6
-
-
-
-
x
HbA1c
x
-
-
-
-
-
-
x
-
-
-
-
-
-
x

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1 Prescription date; 2 Month and year; 3 Treatment given in hospitals (no full coverage); 4 No primary care data; 5 Only type of medication; 6 Partial availability based on 
applicable diagnosis codes; 7 Only chronic diseases included in the special reimbursement scheme; 8 Start and end dates of the special reimbursement; 9 In case a special 
reimbursement was included in the purchase
AvoHILMO=Register of primary health care visits, BMI=body mass index, CPRD=Clinical Practice Research Datalink, DDD=Defined daily dose, EMR=electronic medical 
record, HbA1c=Glycated haemoglobin A1c, HES=Hospital Episode Statistics (Outpatient data, and Admitted Patient Care data), HILMO=Care register for health care; UK 
=The United Kingdom

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8.4.1
The United Kingdom Clinical Practice Research Datalink (CPRD)
The UK CPRD data contains the anonymised longitudinal medical records managed by GPs 
working in the National Health Service (NHS) primary care setting. The data contains 
demographic information, diagnoses, prescriptions, tests and referrals. This study will use 
data extracted from CPRD GOLD [R16-1231] and CPRD Aurum [R19-1534].
CPRD GOLD
CPRD GOLD data [R16-1231] cover approximately 8.8% of the UK population, including 
practices in England, Wales, Scotland and Northern Ireland. Data has been collected 
prospectively since 1987. Approximately 54% of CPRD GOLD practices take part in the 
English linkage program (CPRD GOLD-HES subset), which includes patient-level linkage to 
the inpatient data (HES), allowing for hospitalization diagnoses and procedures to be 
captured [R19-2928]. Records in both settings include the unique NHS number, which is 
used for linkage purposes. In a similar way, CPRD GOLD data is linked to the UK mortality 
data (including date and cause of death). Protocols using CPRD GOLD and linked data are 
subject to approval by an Independent Scientific Advisory Committee. 
CPRD Aurum
CPRD Aurum was established in October 2017 [R19-1534], and therefore, its feasibility 
could not be assessed before starting the present study.
CPRD Aurum data cover approximately 13% of the population in England (as of September 
2018) [R19-1534]; however, recruitment of additional practices is ongoing. Similar to CPRD 
GOLD, the data available in CPRD Aurum can be linked with other data sources using the 
NHS number. In total, 93% of the participating practices take part in the linkage program 
(R19-2928). The same variables are available in CPRD GOLD and in CPRD Aurum.
The main difference between CPRD Aurum and CPRD GOLD is that the data has been 
recorded from different practices using different software [R19-1534]. As practices migrate 
from one software to the other, they will also migrate from the GOLD database to the Aurum 
database. Duplicate historical data will then be available for patients from these practices in 
both GOLD and Aurum. This possibility will be taken into account as both CPRD GOLD and 
CPRD Aurum data are incorporated in this study. The data holder (CPRD) will provide a list 
of migrated (GOLD to Aurum) practices. As Aurum will provide the longest follow-up, the 
data of patients from migrating practices present in both databases will be removed from the 
GOLD data but retained in the Aurum data. 
Linkage
Based on the feasibility assessment before this study, the UK data sources evaluated (CPRD 
GOLD and data with potential for linkage - HES, ONS mortality statistics) met the minimal 
data requirements (Table 5). Similar results were expected for the CPRD Aurum. The 
following UK data sources are considered for linkage with CPRD: HES (Outpatient data and 
Admitted Patient Care data), and Office for National Statistics (ONS) mortality sources. In
the UK, the full study data including follow-up period until the end of 2021, will be available 

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in March 2022. The primary analyses will be based on CPRD GOLD and CPRD Aurum data; 
sensitivity analyses may include linked HES (Outpatient and Admitted Patient Care data) and
ONS data, if linked data with sufficient sample size during the study period are available 
(Section 8.7.2.3.3).
To determine renal impairment, eGFR values will be extracted from CPRD. Additionally, 
information on important covariates such as proxies of socioeconomic position, number of 
albuminuria tests, blood pressure measurements will be extracted. 
8.4.2
Swedish national registries
Sweden has a well-developed population-wide register system with longitudinal follow-up 
data. The persons are identified in the registers with a unique personal identification number 
(PID) and thus the records can be linked for research purposes on subject level between the 
registers. Permissions to use the data may be received upon providing a research plan to the 
authorities responsible for the registers. The protocol is also subjected to relevant Ethical 
Committee´s review and approval. The data permit processes and timelines for data permit 
granting by the authorities responsible for the registers vary between different registers and 
countries, as well as the requirements for the local research collaboration and the publication 
of results [R15-4861].
The nationwide prescription register contains information on outpatient medication purchases 
in pharmacies. All prescribed medicines purchased in community pharmacies are included 
irrespective of reimbursement status. 
Based on the feasibility assessment, the Sweden national registers met the minimal data 
requirements (Table 5). The following data sources will be used to construct the Sweden 
cohort by linkage: The National Patient Register, the Swedish Prescribed Drug Register, the 
Swedish Cancer Register, the Causes of Death Register, the National Diabetes Register, and 
the Longitudinal integration database for health insurance and labour market studies.
To determine renal impairment, eGFR values will be extracted from the National Diabetes 
Register. Information on important covariates such as number of albuminuria tests and blood 
pressure measurements will also be extracted from the National Diabetes Register. Further, 
proxies of socioeconomic position will be obtained from the Longitudinal integration 
database for health insurance and labour market studies.
The study data will be extracted from the relevant registers using the following general 
process. First, patients in the study cohort with the unique PID number are identified from the 
prescription register. A unique dummy study identification number (SID) is created for each 
PID by the prescription register holder. The list with the PID-SID pairs will be provided from 
the prescription register holders to the other register holders. Each register holder extracts the 
relevant data according to the study protocol and links the data to the PID-SID list. 
Subsequently, the register holders decode the data by destroying the key between the PID and 
SID permanently and provides the de-identified study data to the applicant. Thus, only de-
identified data will be provided for performing the analysis of the study data. In Sweden, the
full study data including follow-up period until the end of 2020 will be available during in 
March 2022.

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8.4.3
Finnish data sources
An additional, feasible data source in Europe includes the national registers in Finland, which 
were evaluated in the feasibility assessment before this study.
As in Sweden, Finland has a well-developed population-wide register system with 
longitudinal follow-up data. The persons are identified in the registers with a unique PID and 
thus the records can be linked for research purposes on subject level between the registers. 
Further, the data obtained from registers can be linked with data obtained from the EMR
databases.
The following Finnish nationwide data sources will be included: Care register for health care 
(HILMO), Register of primary health care visits (AvoHILMO), Special reimbursement 
register, Prescription register, Cause of death register, Cancer register, Population register 
centre, and Statistics Finland (Table 5). HILMO and AvoHILMO include diagnoses 
associated with healthcare encounters in specialized and primary care, respectively. The 
Special reimbursement register will be used for identification of chronic comorbidities. This 
register includes patients who are entitled for special refunds of medicine expenses based on 
their chronic conditions. The Finnish nationwide Prescription register contains information 
on outpatient medication purchases in pharmacies. The register contains information on all 
purchased prescribed medicines within the reimbursement scheme. Cause of death register 
includes time of death and the cause of death classified according to the ICD categorization. 
Cancer register includes information on all diagnosed cancers, details of the tumour, and 
description of treatment.
The study data will be extracted from these registers using the general process as described 
above for Sweden (Section 8.4.2). Information about highest level of education will be 
obtained as a proxy for socioeconomic status from Statistics Finland, and information on
patient’s place of residence and migration will be obtained from Population register centre.
Further, to obtain data on important potential confounders, specifically BMI, blood pressure,
smoking, and laboratory measures such as HbA1c and eGFR, EMR databases will also be 
included in the study. Four regional EMR databases (Helsinki, Espoo, Vantaa, and Helsinki 
University Hospital [HUS] area), covering both primary and secondary care in the capital 
area of Finland, will be contacted separately to obtain access to their data. The data obtained 
from different data sources will be linked as described previously (Section 8.4.2).
Permissions to use the data may be received upon providing a research plan to the authorities 
responsible for the registers. The protocol is also subjected to relevant Ethical Committee´s 
review and approval. The data permit processes and timelines for data permit granting by the 
authorities responsible for the registers vary between different registers and countries, as well 
as the requirements for the local research collaboration and the publication of results 
[R15-4861].
In Finland, all the data will be delivered to and analysed in the remote access server 
environment provided by the national permit authority Findata. The data holders will extract 
the relevant data and deliver it to Findata for pseudonymization. Before data delivery to the 

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Findata server environment, the data holders will collect and manage data according to their 
own standards. After the data is delivered to the Findata server environment by the data 
holders, 
 will process the data.
 will use the study identification numbers for data linkage on individual level. 
 will have access to pseudonymized raw data without PINs. Therefore, the 
researchers at 
 will have access to data where individuals cannot be directly 
identified.
In Finland, the full study data including follow-up period until the end of 2020 will be 
available in June 2022.
8.4.4
Additional potential data sources
Beside the data sources evaluated originally in the UK, Sweden, and Finland, none of the 
holders of other databases have been contacted for participation in the study so far, and 
further feasibility assessments are required to insure the validity of urinary cancer case 
identification. It is important for the choice of the appropriate data source to have the 
appropriate information on cancer and important risk factors included. 
Potential additional data sources for this study have been assessed (Annex 1). In addition to 
those described above, Danish nationwide registers, PHARMO Database Network 
(Netherlands), Spanish regional registers, and Maccabi Healthcare Services database (Israel)
are feasible for inclusion in the study. 
8.5
STUDY SIZE
The study size will be driven by the uptake of empagliflozin and the primary comparator 
(DPP-4 inhibitors) in the UK, Sweden, and Finland. Originally, it was expected that by the 
end of 2019, approximately 18,000 empagliflozin-treated patients will accumulate in the 
CPRD and Swedish databases. However, based on the conservative estimates from the fifth 
interim analysis (Annex 1), the expected sample size is higher than anticipated. Taking into 
account the addition of Finland, the addition of CPRD Aurum, and the extension of the study 
period (end of 2020 for Sweden and Finland, end of 2021 for CPRD), a total of
approximately 67,490 empagliflozin users are expected to be eligible for inclusion in the 
study (Table 6). However, the number of patients available for analysis may be lower. Given 
the observed patient numbers, it is expected that the maximum achievable matching ratios 
will be 1:3 for UK CPRD (GOLD and Aurum), 1:1 for Sweden, and 1:2 for Finland.

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Table 6
Observed and expected number of patients eligible for inclusion 
in the study population, by study drug group (including fixed-
dose combinations with metformin), by study country and 
overall, using an arithmetic growth assumption.
Year
Study drug group
Finland
Sweden
CPRD GOLD
CPRD 
Aurum4
Pooled
20141
Empagliflozin
0
0
5
5
DPP 4-inhibitors
5,824
3,214
2,555
11,593
Other SGLT-2 inhibitors
127
662
683
1,472
20151
Empagliflozin
91
629
157
877
DPP 4-inhibitors
14,130
10,305
6,851
31,286
Other SGLT-2 inhibitors
320
1,537
2,065
3,922
20161
Empagliflozin
2,201
2,181
897
5,279
DPP 4-inhibitors
11,391
12,126
5,648
29,165
Other SGLT-2 inhibitors
1,463
1,183
1,740
4,386
20171
Empagliflozin
3,725
4,811
1,391
9,927
DPP 4-inhibitors
7,402
13,677
4,577
25,656
Other SGLT-2 inhibitors
1,475
1,191
1,493
4,159
20181
Empagliflozin
4,293
8,738
1,536
14,567
DPP 4-inhibitors
6,959
12,798
4,158
23,915
Other SGLT-2 inhibitors
1,610
1,030
1,470
4,110
20191
Empagliflozin
5,182
10169
1,846
17,197
DPP 4-inhibitors
6,158
11,673
3,622
21,453
Other SGLT-2 inhibitors
1,853
1,061
1,665
4,579
20202
Empagliflozin
2,777
5,806
1,541
10,124
DPP 4-inhibitors
2,215
4,688
2,210
9,113
Other SGLT-2 inhibitors
1,201
653
1,369
3,223
20213
Empagliflozin
969
DPP 4-inhibitors
1,051
Other SGLT-2 inhibitors
726
Total
Empagliflozin
18,269
32,334
8,342
8,545
67,490
DPP 4-inhibitors
54,079
68,481
30,672
59,283
212,515

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Year
Study drug group
Finland
Sweden
CPRD GOLD
CPRD 
Aurum4
Pooled
Other SGLT-2 inhibitors
8,049
7,317
11,211
25,277
51,854
1 Observed number of patients.
2 Observed number of patients until 30th June for Sweden and Finland and until 31st December for UK CPRD GOLD, 
taking into account the extension of the study period to the end of 2021 for UK CPRD.
3 Expected  number of patients (arithmetic growth assumption given observed numbers in previous years) between 1st 
January  and 30th June, taking into account the 6 months minimum follow-up. 
4 Only aggregate level data up (2014-2020) of was available for CPRD Aurum. Patient numbers were extrapolated based on 
assumptions derived from CPRD GOLD data, taking into account the extension of the study period to the end of 2021
DPP-4=dipeptidyl peptidase-4 inhibitors; SGLT-2=sodium glucose co-transporter-2 inhibitors; UK=the United Kingdom
The power to detect relative risks of 1.5 and 2 was determined for each of the study outcomes
for each individual country (Table 7) and for the final random-effects meta-analysis (Table 
8). For the single-country analyses, power computations were based on HRs derived from
Cox models. For the meta-analysis, simulations were used to estimate country-level HRs
which were then entered into random-effects meta-analysis models as described in Section 
8.7.1.4. All power computations were based on the expected number of individuals exposed 
to empagliflozin eligible for inclusion in the study and the observed country-level IRs of 
urinary tract cancers, bladder cancer and renal cancer in the study population as reported in 
the 5th Interim Report. The expected averages of follow-up time were 2.4 years for UK
CPRD, 2.2 for Sweden, and 2.4 for Finland, as reported in the 5th Interim Report. Matching 
ratios of empagliflozin initiators to initiators of DPP-4 inhibitors were fixed at 1:3 for UK
CPRD, 1:1 for Sweden, and 1:2 for Finland. These are the highest achievable matching ratios 
given expected patient numbers. For computing the meta-analysis power, these assumptions 
were used to simulate for each country separately individual level time-to-event data from 
each drug cohort following an exponential distribution given the expected number of 
empagliflozin initiators, the expected matching ratio, the observed incidence rates as the 
baseline rate in the DPP-4 cohort. The hazard ratio for each simulation run was determined 
by drawing from a normal distribution with a mean of the natural logarithm of the target 
hazard ratio (1.5 or 2.0) and a standard deviation of 0.1. These individual time-to-event data 
were then entered into a Cox proportional hazard model for each country to compute a 
simulated hazard ratio. For each simulation, the country-level hazard ratios were entered into 
a random-effects meta-analysis level, and the resulting p-value of the pooled estimate was
retained. Simulations were run 500 times and power was computed as the proportion of 
simulations for which the p-value of the pooled estimate was inferior to 0.5. 
The power calculations show that anticipated study sample size would ensure sufficient 
power at the meta-analysis level to detect the targeted effect size of < 1.6 for urinary tract 
cancers and bladder cancer and the targeted effect size of < 2.0 for renal cancer, with at least 
80% power and a type 1 error probability of 5% under the expected matching ratios. Power at 
the meta-analysis level to detect an effect size of 1.5 is expected to be of 93.6% for urinary 
tract cancer and 84.0% for bladder cancer. Power at the meta-analysis level to detect an effect 
size of 2.0 is expected to be of 97.0% for renal cancer.

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Table 7
Power for different effect sizes for single-country analyses 
based on Cox models with a type 1 error probability of 5%,
given country-level observed incidence rates, expected numbers
of empagliflozin initiators, expected follow-ups, and expected 
matching ratios.
Effect size
(Hazard ratio)
Urinary tract 
cancer
Bladder 
cancer
Renal cancer
UK CPRD1
1.5
63.7%
43.1%
20.3%
2.0
99.1%
91.7%
55.9%
Sweden2
1.5
85.1%
66.6%
42.9%
2.0
>99.9%
99.0%
89.4%
Finland3
1.5
80.6%
54.3%
46.7%
2.0
99.9%
96.8%
93.4%
1 Includes both CPRD GOLD and Aurum; Observed IRs of 111.5, 66,7, and 26.5 per 100,000 person-years for UTC, 
bladder cancer, and renal cancer respectively, expected follow-up of 2.4, matching ratio of 1:3, and expected number 
of empagliflozin initiators of 16,360.
2 Observed IRs of 164.5, 104.1, and 58.0 per 100,000 person-years for UTC, bladder cancer, and renal cancer respectively, 
expected follow-up of 2.2, matching ratio of 1:1, and expected number of empagliflozin initiators of 32,334.
3 Observed IRs of 161.5, 86.8, and 71.6 per 100,000 person-years for UTC, bladder cancer, and renal cancer respectively, 
expected follow-up of 2.4, matching ratio of 1:2, and expected number of empagliflozin initiators of 18,269.
UK CPRD=The United Kingdom Clinical Practice Research Datalink
Table 8
Power of meta-analyses for a type 1 error probability of 5% for 
different effect sizes, given country-level observed incidence 
rates, expected number of empagliflozin initiators, expected 
average follow-ups, and expected matching ratios.
Effect size
(Relative risk / 
hazard ratio)
Urinary tract cancer
Bladder cancer
Renal cancer
1.5
93.6%
84.0%
68.2%
2.0
>99.9%
99.6%
97.0%
For UK CPRD (GOLD and Aurum): observed IRs of 111.5, 66,7, and 26.5 per 100,000 person-years for UTC, bladder 
cancer, and renal cancer respectively, expected follow-up of 2.4, matching ratio of 1:3, and expected number of 
empagliflozin initiators of 16,360.
For Sweden: observed IRs of 164.5, 104.1, and 58.0 per 100,000 person-years for UTC, bladder cancer, and renal cancer 
respectively, expected follow-up of 2.2, matching ratio of 1:1, and expected number of empagliflozin initiators of 
32,334.

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For Finland: observed IRs of 161.5, 86.8, and 71.6 per 100,000 person-years for UTC, bladder cancer, and renal cancer 
respectively, expected follow-up of 2.4, matching ratio of 1:2, and expected number of empagliflozin initiators of 
18,269.
The minimum detectable effect sizes for each outcome were computed given the observed
and expected IRs, average follow-ups, matching ratios, and number of empagliflozin 
initiators for single-country analyses as well as for a random-effects meta-analysis (Table 9). 
At the meta-analysis level, the minimum detectable effect sizes were 1.37 for urinary tract 
cancers, 1.47 for bladder cancer, and 1.62 for renal cancer.
Table 9
Minimum detectable effect sizes (Hazard Ratios) given country-
level observed incidence rate, expected sample sizes, expected 
average follow-ups, and matching ratios for single-country
analyses and meta-analyses for a type 1 error probability of 5%.
Urinary tract cancer
Bladder cancer
Renal cancer
UK CPRD1
1.62
1.82
2.40
Sweden2
1.46
1.60
1.85
Finland3
1.50
1.70
1.78
Meta-analysis
1.37
1.47
1.62
1 Includes both CPRD GOLD and Aurum; Observed IRs of 111.5, 66,7, and 26.5 per 100,000 person-years for UTC, 
bladder cancer, and renal cancer respectively, expected follow-up of 2.4, expected number of empagliflozin initiators 
of 16,360, and matching ratio of 1:3.
2 Observed IRs of 164.5, 104.1, and 58.0 per 100,000 person-years for UTC, bladder cancer, and renal cancer respectively, 
expected follow-up of 2.2, expected number of empagliflozin initiators of 32,334, and matching ratio of 1:1.
3 Observed IRs of 161.5, 86.8, and 71.6 per 100,000 person-years for UTC, bladder cancer, and renal cancer respectively, 
expected follow-up of 2.4, expected number of empagliflozin initiators of 18,269, and matching ratio of 1:2.
UK CPRD=The United Kingdom Clinical Practice Research Datalink
The study sizes for each individual country required to detect a relative risk of 1.5 and 2.0, 
with 80% power under the expected country-level matching ratios and observed country-level 
IRs were computed for each study country individually (Table 10) and for a random-effects
meta-analysis (Table 11). At the meta-analysis level, the required country-level sample sizes 
to detect an effect size of 1.5 for urinary tract cancer are 9,076, 17,377, and 9,818 for UK
CPRD, Sweden, and Finland, respectively. For detecting an effect size of 2.0 for renal cancer 
at the meta-analysis level, the required sample sizes are 6,534, 12,510, and 7,069 for UK
CPRD, Sweden, and Finland, respectively.

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Table 10
Required sample sizes in each study country to estimate 
different effect sizes for the three primary endpoints in the 
single-country analyses with at least 80% power and a type 1 
error probability of 5%, given country-level incidence rates, 
expected average follow-ups, and expected matching ratios.
Primary 
endpoints
HR=1.5
HR=2
UK
CPRD1
(1:3)
Sweden2
(1:1)
Finland3
(1:2)
UK
CPRD1
(1:3)
Sweden2
(1:1)
Finland3
(1:2)
All Urinary 
tract cancers
25,810
28,151
17,999
7,072
8,665
5,276
Bladder 
cancer 
41,550
44,523
33,543
11,846
13,707
9,835
Renal cancer 104,474
79,991
40,665
29,788
24,630
11,924
1 Includes both CPRD GOLD and Aurum; Observed IRs of 111.5, 66,7, and 26.5 per 100,000 person-years for UTC, 
bladder cancer, and renal cancer respectively and expected follow-up of 2.4.
2 Observed IRs of 164.5, 104.1, and 58.0 per 100,000 person-years for UTC, bladder cancer, and renal cancer respectively
expected follow-up of 2.2.
3 Observed IRs of 161.5, 86.8, and 71.6 per 100,000 person-years for UTC, bladder cancer, and renal cancer respectively
expected follow-up of 2.4.
HR=Hazard ratio; UK CPRD=The United Kingdom Clinical Practice Research Datalink

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Table 11
Required sample sizes in each study country to estimate 
different effect sizes for the three primary endpoints in the 
meta- analyses with at least 80% power and a type 1 error 
probability of 5%, given country-level incidence rates, expected 
average follow-ups, and expected matching ratios.
Primary 
endpoints
HR=1.5
HR=2.0
UK
CPRD1
(1:3)
Sweden2
(1:1)
Finland3
(1:2)
UK
CPRD1
(1:3)
Sweden2
(1:1)
Finland3
(1:2)
All Urinary 
tract cancers 
9,076
9,076
9,076
2,561
4,903
2,770
Bladder 
cancer 
15,505
29,687
16,773
4,058
7,769
4,390
Renal cancer 25,252
48,350
27,318
6,534
6,534
6,534
1 Includes both CPRD GOLD and Aurum; Observed IRs of 111.5, 66,7, and 26.5 per 100,000 person-years for UTC, 
bladder cancer, and renal cancer respectively and expected follow-up of 2.4.
2 Observed IRs of 164.5, 104.1, and 58.0 per 100,000 person-years for UTC, bladder cancer, and renal cancer respectively 
expected follow-up of 2.2.
3 Observed IRs of 161.5, 86.8, and 71.6 per 100,000 person-years for UTC, bladder cancer, and renal cancer respectively 
expected follow-up of 2.4.
HR=Hazard ratio; UK CPRD=The United Kingdom Clinical Practice Research Datalink
The average follow-up time required to achieve 80% power to detect HRs of 1.5 and 2.0 with 
the expected number of patients (Table 6) and observed IRs was evaluated for each of the 
study outcomes for the country-level analyses (Table 12) and for a random-effects meta-
analysis (Table 13). 

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Table 12
Required follow-up time (years) to achieve 80% power in 
country-level analyses with a type 1 error probability of 5% for 
different effect sizes for the three primary endpoints given
country-level observed incidence rates, expected sample sizes, 
and expected matching ratios
Matching
Hazard ratio
Urinary tract 
cancer
Bladder cancer
Renal cancer
UK CPRD1
1:3
1.5
3.03
4.73
11.13
2.0
1.22
1.71
3.54
Sweden2
1:1
1.5
1.99
2.86
4.73
2.0
0.96
1.23
1.81
Finland3
1:2
1.5
2.38
4.00
4.75
2.0
1.05
1.53
1.75
1 Includes both CPRD GOLD and Aurum; Observed IRs of 111.5, 66,7, and 26.5 per 100,000 person-years for UTC, 
bladder cancer, and renal cancer respectively, expected number of empagliflozin initiators of 16,360, and matching 
ratio of 1:3.
2 Observed IRs of 164.5, 104.1, and 58.0 per 100,000 person-years for UTC, bladder cancer, and renal cancer respectively, 
expected number of empagliflozin initiators of 32,334, and matching ratio of 1:1.
3 Observed IRs of 161.5, 86.8, and 71.6 per 100,000 person-years for UTC, bladder cancer, and renal cancer respectively, 
expected number of empagliflozin initiators of 18,269, and matching ratio of 1:2.
UK CPRD=The United Kingdom Clinical Practice Research Datalink

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Table 13
Required follow-up time (years) in each study country to 
achieve 80% power for the meta-analysis with a type 1 error 
probability of 5%for different effect sizes for the three primary 
endpoints given country-level observed incidence rates, 
expected sample sizes, and expected matching ratio 
Matching
Hazard ratio
Urinary tract 
cancer
Bladder cancer
Renal cancer
UK CPRD1
1:3
1.5
1.38
2.05
3.08
2.0
0.74
0.91
1.20
Sweden2
1:1
1.5
1.38
2.04
3.07
2.0
0.74
0.91
1.20
Finland3
1:2
1.5
1.50
2.22
3.35
2.0
0.81
0.99
1.31
1 Includes both CPRD GOLD and Aurum; Observed IRs of 111.5, 66,7, and 26.5 per 100,000 person-years for UTC, 
bladder cancer, and renal cancer respectively, expected number of empagliflozin initiators of 16,360, and matching 
ratio of 1:3.
2 Observed IRs of 164.5, 104.1, and 58.0 per 100,000 person-years for UTC, bladder cancer, and renal cancer respectively, 
expected number of empagliflozin initiators of 32,334, and matching ratio of 1:1.
3 Observed IRs of 161.5, 86.8, and 71.6 per 100,000 person-years for UTC, bladder cancer, and renal cancer respectively, 
expected number of empagliflozin initiators of 18,269, and matching ratio of 1:2.
UK CPRD=The United Kingdom Clinical Practice Research Datalink
Based on the feasibility assessment before this study and the interim reports, utilization of 
empagliflozin in the UK and Sweden is still low. Accrual of empagliflozin users is monitored 
in the data sources as described in Section 8.7.1.7. The number of users in each treatment 
cohort has been monitored at 24 months after empagliflozin use started being captured in the 
UK and Swedish data sources (November 2016) and has and will be monitored annually 
thereafter until November 2020. The numbers were reported in annual interim reports in the 
1st quarter of years 2017-2021 and the results of the interim reports were submitted to EMA 
by the Sponsor within the earliest corresponding PBRER. Initially, this study included two 
countries, the UK (CPRD GOLD) and Sweden, with follow-up until 31st December 2019. In 
order to increase the accumulated patient years and number of patients initiating the study 
drugs as well as accounting for the long latency period related to risk of malignancies, the 
study follow-up was first extended until 31st December, 2020 and Finnish national registers 
were included. Additionally, in this version of the protocol (Version 7.0) CPRD Aurum was 
included and the study period for both CPRD databases was extended to 31st December, 
2021 in order to further increase the sample size and follow-up, and, consequently, study 
power. 

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8.6
DATA MANAGEMENT
Full audit trail starting from raw data obtained from register holders and ending with 
statistical tables and graphs in reports will be maintained. Data management, tabulations, 
graphics, and statistical modelling will be carried out with R data analyses language 
(http://www.r-project.org). R language is described more detailed in report "R: Regulatory 
Compliance and Validation Issues: A Guidance Document for the Use of R in Regulated 
Clinical Trial Environments" (http://www.r-project.org/doc/R-FDA.pdf). Source code of data 
management and data analyses is kept for inspection for five years after publication of 
results. The study may be inspected by the sponsor’s study independent representative(s) or 
inspected by the competent authorities. A SEAP detailing all statistical analyses will be 
drawn and used as a basis for analysis. 
Data from multiple country sources will be sent utilizing password protected media. All study 
related datasets will be stored in secured server environment. Access to data will be permitted
only to study statisticians and data managers in line with the data permits. All data used for 
this study will be anonymous such that no study individual can be directly identified. Data 
will be regularly backed-up and stored in a separate secure location. All data and back-ups 
will be maintained within the EU.
8.7
DATA ANALYSIS
The final approach to data analysis will be presented in a separate SEAP to be developed 
prior to the start of data analysis. The SEAP will include a detailed algorithm for identifying 
T2D patients, detailed methods for covariate selection, checking for empirical equipoise, 
model checking for outcome models, methods for time-dependent exposure and time-varying 
confounding, the approaches for handling missing data, the assessment of the potential 
impact of unmeasured confounding, and the critical sensitivity analyses. The SEAP will be 
made available upon request to EMA and will be included or appended in the study report.
8.7.1
Main analysis
For the primary, secondary and further objectives, the main data analysis will be conducted in 
two stages: (i) construction of the PS-matched cohort by modelling the exposure to 
empagliflozin vs. DPP-4 inhibitors and (ii) estimating the effect of exposure to empagliflozin
on the urinary tract (bladder, renal and other) cancers using aHRs and IRs compared to those 
exposed to DPP-4 inhibitors. Additional sensitivity analyses will be performed to validate the 
robustness of alternative definitions of outcome, exposure, covariates and reduction of bias 
due to matching.
8.7.1.1
Matching at index date
For all individuals, PS for the comparison of empagliflozin vs DPP-4 inhibitors will be 
computed at the index date as the probability to receive empagliflozin conditional on 
treatment and clinical history up to index date within each stratum. The PS will be estimated

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using a binary logistic regression model. Depending on sample size, combination exposures 
with metformin will be accounted for through separate PS, stratification, or adjustment.
The selection of variables to be included in the PS models (see Section 8.3.3) will be based 
on scientific basis from previous studies, clinical/epidemiological significance and
examination of exposure group differences in the distribution of each covariate. The 
covariates included in the PS model should ideally be associated with the outcomes of 
interest. Simulation studies show that variables that are unrelated to the exposure but are 
related to the outcome should always be included in the estimation of PS [R12-1913]. 
Inclusion of these variables increases the precision of the estimated effect of exposure 
without increasing bias. In contrast, inclusion of variables that are related to the exposure but 
not to the outcome can decrease precision of the estimated effect of exposure without 
decreasing bias. The variables listed in Annex 6 are potential candidates for inclusion in the 
PS model. Depending on sample size, combination exposures with metformin and treatment 
complexity (monotherapy, dual combination therapy, triple combination therapy) will be 
accounted for through separate PS, stratification, or adjustment.
Matching will be performed for empagliflozin initiators with patients initiating DPP-4 
inhibitors within each country database. Matching will be carried out in several rounds to 
achieve the highest possible matching ratio given the available data in each country (up to 1:3 
matching) [P12-07757]. In the first round of matching, for each empagliflozin initiating 
individual i with a particular index date TiE, all individuals initiating other DPP-4 inhibitors
within three months before or after TiE will be chosen. Of these, one individual with the 
closest PS to that of i within a predefined PS interval will be selected as a match (Greedy 
matching method). The predefined PS interval will be calculated based on the standard 
deviation of the logit of PS (δ) multiplied by some coefficient k (say, kδ, when k=0.2). The 
value of the coefficient k will be calibrated to ensure at least 99% of those exposed to 
empagliflozin have matches from each comparator. The selected comparators are then 
removed from the pool of the possible comparators for further selection (sampling without 
replacement). Once the first round of matching is done, additional rounds of matching will be 
carried out to identify a second and possibly a third match for each already matched for each 
empagliflozin initiating individual (variable ratio matching with 1:3 as the maximum ratio).
The number of matched DPP-4 inhibitors, and hence the overall matching ratio, will therefore 
be maximized within each country. Matching by time period, based on index dates, enables 
better control of time-varying confounders including changing prescription patterns for 
empagliflozin and potential confounding.
8.7.1.2
As-treated (AT) analysis
For the incident users of empagliflozin along with their respective matches, the primary 
analysis will be performed using the AT approach. This corresponds to censoring individuals 
who discontinue use of the index drug, i.e., either switch from the index drug to other drugs
(empagliflozin, DPP-4 inhibitors, or other SGLT-2 inhibitors) during follow-up, or stop using
the index drug (see Section 8.3.4).

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8.7.1.3
Population summary and descriptive analyses
Univariate and bivariate distribution of exposures, outcomes and relevant covariates will be 
presented using absolute and relative frequencies for categorical variables and summary 
measures for continuous variables (mean, standard deviation, median, min, max). Bivariate 
distributions for outcomes and covariates will be with reference to primary exposure 
definitions.
Absolute risks (IRs) for the defined outcomes will be estimated within each exposure 
category and key covariates using Poisson regression. The IRs will be presented along with 
95% CIs. Other descriptive summaries such as number of events and person-time for 
calculating the IR will be included. 
Kaplan-Meier plots, with 95% CIs, for survival probabilities will be presented for all urinary 
tract cancers, bladder cancers and renal cancers with primary exposures using the AT
definition of follow-up times.
8.7.1.4
Comparative analyses
Relative risks (HRs) for the defined outcomes will be estimated using Cox models with time-
varying covariates if model pre-requisites are fulfilled. HRs will be presented along with 95% 
CIs. 
The Cox models will include the exposure and the comparator group within the model. This 
will account for multiple testing and for retaining same variables in variable selection (see 
Section 8.7.1.6). The models are defined in terms of covariates adjusted for in addition to the 
primary exposure: (i) baseline model with covariates adjusted for with values at index date 
(ii) model with time-dependent covariates wherein change in covariates over the follow-up 
period after index date are also incorporated into the model.
Country-specific analysis: 
The country-specific Cox models will be fit with single-country level datasets. The analyses 
will use datasets from the UK, Sweden, and Finland, separately.
Meta-analysis:
Country-level effect sizes will be pooled using meta-analysis models to compute pooled 
effect size estimates. Prior to conducting meta-analyses, heterogeneity across the countries in 
terms of study design and conduct will be assessed. Specifically, the variability in population 
characteristics (including data availability), propensity score matching variables as well as 
propensity score balance will be examined. 
Meta-analyses will be carried out for analyses where the country-level effect size is available 
for all three study countries. Pooled effect sizes will be estimated using random-effects 
models. The inverse-variance method will be used where appropriate.

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Statistical heterogeneity between country-level estimates will be assessed using:

Cochran’s Q test 

I2 statistic and its 95% CI

The τ2 statistic and its 95% CI
For each meta-analysis model, results will be presented in a forest plot including at least the
following data: 

Data source.

Effect size and 95% CI for each study included in the analysis (on a log scale).

The weights allocated to each study.

The combined estimated effect size with 95% CI (on a log scale) for the random-
effects model.

Value of Cochran’s Q statistic, with the number of degrees of freedom and p-value.

The proportion of variability explained by heterogeneity (I2).

The between-study variance τ2.
If high levels of heterogeneity exist, the population characteristics and statistical models in 
the different country-level analyses will be reviewed and the possible source of heterogeneity 
discussed. A sensitivity analysis for the main analysis of the primary outcomes will be carried 
out using fixed-effect models to ascertain the effect of between-study heterogeneity on the 
meta-analysis result.
Further details regarding the meta-analysis models and heterogeneity will be defined in the 
study SEAP.
8.7.1.5
Variable selection
All potential confounders, exact and PS matching variables will enter the outcome model 
only after being selected using predefined variable selection criteria to be detailed in the 
SEAP. 
8.7.1.6
Monitoring of accrual of empagliflozin users 
Accrual of empagliflozin users, free or fixed-dose combinations with metformin, has been
monitored starting at 24 months after use of empagliflozin was first captured in the UK and 
Swedish data sources (November 2016), and the numbers will be monitored annually until 
2020. The purpose of this monitoring is to estimate the event rates for the outcomes of 
interest to confirm the event rates described in the literature and used in the sample size 
analyses. Finland was added in protocol version 5.0 and the final report will include data 
from the UK CPRD GOLD, CPRD Aurum, and National registers in Sweden and Finland.
The available power to estimate the association between empagliflozin use and the outcomes 
will be examined. If there is insufficient power (<80%) because, given the current event rates, 
the number of new users of empagliflozin accrued up to that point is too low to yield 
acceptable precision, decisions will be made about extending the length of the study period, 
the need to use additional country data sources, and/or changing the primary study design to a 
nested case-control study.

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8.7.1.7
Handling of missing data
A high frequency of missing values is not expected for most variables, with the possible 
exception of lifestyle and laboratory parameters. For the medical history conditions/ 
comorbidities to be collected for inclusion in the PS, 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 (CPRD GOLD or Aurum, Sweden or Finland), 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.

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8.8
QUALITY CONTROL
The study will be conducted as specified in this protocol and SEAP. All revisions to the 
protocol shall be properly documented as protocol changes/amendments and when necessary,
such protocol amendments will be delivered to register holder(s) whenever amendment(s) to 
the data permissions are required. 
The study protocol has been written by following the Code of Conduct by the European 
Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP)
[R15-4870] that provides a set of rules and principles for post-authorisation studies with 
regard to the best practices and transparency, thereby promoting scientific independence of
such studies. ENCePP is a project led by the EMA to further strengthen the post-authorisation 
monitoring of medicinal products in Europe by facilitating the conduct of multi-centre, 
independent, post-authorisation studies focusing on safety and on benefit/risk. The study will 

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be registered to the ENCePP’s E-register. The results of this study will also be published on 
the same site. 
The study protocol also follows the key elements of the Guideline for Good 
Pharmacoepidemiology Practices by International Society for Pharmacoepidemiology 
[R11-4318], and the recent draft Guidance for Industry and FDA Staff “Best Practices for 
Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic 
Healthcare Data Sets” [R15-4859].
All programs for data management and data analyses will be written by study statistician(s). 
Quality control check of these programs will be carried out by a statistician other than the one 
who writes the program. All processes from data management leading to dissemination of
study results will undergo quality control checks for programs, result tables and written text. 
A detailed audit trail of all documents (programs, result tables, reports) along with quality 
control processes will be maintained.
8.9
LIMITATIONS OF THE RESEARCH METHODS
There are several methodological challenges to conducting epidemiological studies 
evaluating the comparative safety of glucose lowering medications [P12-13528, P14-17457, 
R14-4378, R13-1120, R10-6638].
The last (fifth) interim report (ANNEX 1) presented sample sizes of the study populations. It 
was noted that SGLT-2 inhibitor users were few and so that group was removed from 
analyses as stated in the amendments and updates, Section 4.
The actual use of prescribed or purchased drugs, especially oral glucose lowering
medications cannot be verified with certainty. Drug exposure will be defined by algorithmic 
approaches based on the amount dispensed/prescribed in a prescription. This may be subject 
to misclassification. Sensitivity analyses will be performed to assess the impact of the 
exposure definitions on the main results.
The time-dependent nature of the exposure also creates a challenge due to time-dependent 
confounding. Although PS matching is used to control for imbalances between exposed and 
unexposed cohorts at the time of index date, other factors potentially associated with both 
exposure and outcome after index date are not controlled by PS matching. This may be 
tackled by use of causal models (e.g., marginal structural models, inverse-probability of 
weighting approach) as sensitivity analysis.
The AT approach used as the primary analysis may result in exclusion of cancer cases due to 
censoring at treatment discontinuation of the index drug. This will be addressed in sensitivity 
analyses as an ITT approach will be conducted. The ITT approach is conservative and is 
subject to exposure misclassification, but it ensures the evaluation of all cases occurring
during the study period. For this reason, we will conduct sensitivity analyses considering a 
longer time period after treatment discontinuation. Finally, we will apply a 6-month lag 

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period after the index date to the follow-up time in both the AT and ITT analyses to exclude 
subjects with only a short exposure time. 
Determining the appropriate induction/promotion time window is challenging and typically 
only empirically based. Sensitivity analyses will evaluate a longer latency time window (12 
months).
Although many variables may be included in the study, there will be relatively limited 
information (including age, sex, previous hospitalizations, chronic diseases) about risk factors 
connected to malignancies of UT from the available databases. For example, information on 
exposure to toxic chemicals is not available in the study databases. We attempt to control for 
the confounding bias by using baseline and time-dependent variables of potential 
confounders in the statistical analyses.
A potential limitation of using PS matching is that any exposed patient without a matched 
control would be excluded from the analyses. This will be tackled by applying a wider 
matching caliber for the PS for all unmatched cases after the first round of matching.
8.9.1
Bias
Potential source of difference in cancer incidence may arise due to channelling bias, detection 
bias and confounding. The channelling bias is addressed through both two-stage modelling 
approach wherein individuals are first matched on PS conditional on variables that affect 
exposure and outcome. Confounding will be minimized through model adjustment after 
carefully selecting variables using the variable selection criteria. However, there may be 
confounding due to unobserved variables and/or incomplete adjustment. Detection bias is
inherent in cancer studies, especially those where the outcome is based on cancer notification. 
Although the notification is complete, early stages may go undetected. In studies including 
exposures with publicized safety concerns, diagnostic bias is also a concern, as patients with 
the exposure may be more likely to receive screenings for the outcome. The potential for 
diagnostic bias will be evaluated and addressed through consideration of the frequency of 
urine dipstick testing (as captured through albuminuria tests) and stage of cancer at the time 
of diagnosis (as more early-stage cancers in one group would be suggestive of diagnostic 
bias).
Bias due to definitions of exposure, definition of follow-up times and other relevant 
covariates will be addressed through sensitivity analyses. As mentioned in Section 8.9, the 
AT approach used as the primary analysis is subject to omission of cancer cases due do 
censoring after treatment switch or treatment discontinuation. An ITT approach will therefore 
be used in sensitivity analyses.
8.9.2
Generalizability
In the current study three population-based data sources (CPRD GOLD, CPRD Aurum, and 
Swedish and Finnish national registries) will be used. CPRD GOLD provides data entered by 
primary care practitioners in a routine clinical care setting and covers approximately 8.8% of 

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the UK population and CPRD Aurum about 13% of England population The patients are 
broadly representative of the UK population in terms of age, sex and ethnicity. In Sweden,
the national registries cover practically all patients with T2D. In Finland, the coverage of the 
EMR data is approximately 26.7%, and study population is broadly generalizable. Therefore, 
the study results can be generalized to similar patients with T2D in other geographic settings, 
including most industrialized countries.

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9.
PROTECTION OF HUMAN SUBJECTS
To ensure the full data protection of patients, all the research data in each country is 
anonymised. The implications of the General Data Protection Regulation (EU) 2016/679 on 
the national legislations, during the course of the study, will be considered. Approval from 
relevant Ethical/Research Review Boards will be required before conducting the study.

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10.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
Based on current guidelines from the International Society for Pharmacoepidemiology 
[R11-4318] and the EMA [R13-1970], non-interventional studies such as the one described in 
this protocol, conducted using medical chart reviews or electronic claims and health care 
records, do not require expedited reporting of suspected adverse events/reactions. 
Specifically, as stated in section VI.C.1.2.1 of Guideline on Good Pharmacovigilance 
Practices (GVP), Module VI – Management and Reporting of Adverse Reactions to 
Medicinal Products, for non-interventional study designs, which are based on use of 
secondary data, reporting of adverse reactions is not required.
The data generated in the course of the study will be monitored by the BI responsible person.
When an observation is identified that may qualify as a special safety issue or that may have 
implications for the benefit-risk balance of empagliflozin, appropriate BI functions will be 
notified according to BI standard operating procedures.

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11.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
Study reports will be prepared using a template following the Guideline on Good 
Pharmacovigilance Practices (GVP), Module VIII, Section B.6.3 [R13-5420]. The principal 
and co-investigators will write the annual interim reports and the final study report. The 
reports will be delivered to the Sponsor. The Sponsor will submit the interim and the final 
reports to EMA in line with the milestones (see Section 5) and report the results within the
earliest corresponding PSURs; the final report will be submitted to the EMA as a type II 
variation. The study results will be published in the EU PASS registry.
The principal and co-investigators will co-author scientific manuscript(s) of the results to be
published. The publication strategy is defined in the research agreement between the 
principal investigators and the Sponsor. A summary of the main results of the study, whether 
positive or negative and including results from prematurely terminated studies, will always be 
made available to the public. Per Section V of Guidelines for Good Pharmacoepidemiology 
Practices (GPP) [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 Sponsor is entitled to view the final results and interpretations thereof prior to 
submission for publication and to comment in advance of submission as agreed in the 
research contract and without unjustifiably delaying the publication.

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12.
REFERENCES
12.1
PUBLISHED REFERENCES
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Macedo AF, Douglas I, Smeeth L, Forbes H, Ebrahim S. Statins and the risk of 
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NICE. Type 2 diabetes: the management of type 2 diabetes. NICE clinical 
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Rawson NS. Review of the quality of observational studies of the association 
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Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel 
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Gonzalez EL, Johansson S, Wallander MA, Rodriguez LA. Trends in the 
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Larsson SC, Orsini N, Brismar K, Wolk A. Diabetes mellitus and risk of 
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Carstensen B, Witte DR, Friis S. Cancer occurrence in Danish diabetic 
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Brookhart MA, Schneeweiss S, Rothman KJ, Glynn RJ, Avorn J, Sturmer T. 
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Onitilo AA, Engel JM, Glurich I, Stankowski RV, Williams GM, Doi SA 
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Causes Control 2012; 23:967-981.
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Schneeweiss S. A basic study design for expedited safety signal evaluation 
based on electronic healthcare data. Pharmacoepidemiol Drug Saf 2010; 19 
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Bao C, Yang X, Xu W, Luo H, Xu Z, Su C, Qi X. Diabetes mellitus and 
incidence and mortality of kidney cancer: a meta-analysis. J Diabetes 
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EMA. Guideline on good pharmacovigilance practices (GVP). Module VI –
Management and reporting of adverse reactions to medicinal products. 
European Medicines Agency; 22 June 2012. Available at: website: 
emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/
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NICE. Dapagliflozin in combination therapy for treating type 2 diabetes. NICE 
technology appraisal guidance 288. National Institute for Health and Care 
Excellence;  2013. Available at: website: 
nice.org.uk/guidance/ta288/resources/guidance-dapagliflozin-in-combination-
therapy-for-treating-type2-diabetes-pdf. Accessed 09 October 2014.
R13-5420
EMA. Guideline on good pharmacovigilance practices (GVP). Module VIII –
Post-authorisation safety studies. European Medicines Agency; 9 July 2012. 
Available at: website:
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WC500129137.pdf. Accessed 7 February 2013.

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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.
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Boehringer Ingelheim International GmbH. Jardiance (empagliflozin) 
summary of product characteristics.  2014. Available at: website: 
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pages/medicines/human/medicines/002677/human_med_001764.jsp&mid = 
WC0b01ac058001d124. Accessed 09 October 2014.
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Leal I, Romio SA, Schuemie M, Oteri A, Sturkenboom M, Trifiro G. 
Prescribing pattern of glucose lowering drugs in the United Kingdom in the 
last decade: a focus on the effects of safety warnings about rosiglitazone. Br J 
Clin Pharmacol 2013; 75 (3): 861-8.
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Morgan CL, Poole CD, Evans M, Barnett AH, Jenkins-Jones S, Currie CJ. 
What next after metformin? A retrospective evaluation of the outcome of 
second-line, glucose-lowering therapies in people with type 2 diabetes. J Clin 
Endocrinol Metab 2012; 97 (12): 4605-12.
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Five Continents, Vol. X (electronic version) Lyon, IARC [cited 2015 June 23]. 
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Furu K, Wettermark B, Andersen M et al. The Nordic countries as a cohort for 
pharmacoepidemiological research. Basic Clin. Pharmacol. Toxicol. 2010, 
106:86-94.
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Dregan A, Moller H, Murray-Thomas T and Gulliford MC. Validity of cancer 
diagnosis in a primary care database compared with linked cancer registrations 
in England. Population-based cohort study. Cancer Epidemiol. Elsevier Ltd; 
2012 Oct;36(5):425–9.
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Chow WH, Lindblad P, Gridley G, Nyren O, McLaughlin JK, Linet MS, 
Pennello GA, Adami HO, Fraumeni JF. Risk of urinary tract cancers following 
kidney or ureter stones. J Natl Cancer Inst 1997; 89(19):1453-1457.

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R15-4864
Boggon R, van Staa TP, Chapman M, Gallagher AM, Hammad TA, Richards 
MA. Cancer recording and mortality in the General Practice Research 
Database and linked cancer registries. Pharmacoepidemiol Drug Saf. 2013 
Feb; 22(2): 168–75.
R15-4865
Boffetta P, Jourenkova N, Gustavsson P. Cancer risk from occupational and 
environmental exposure to polycyclic aromatic hydrocarbons. Cancer Causes 
Control 1997; 8(3):444-472.
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Burger M, Catto JWF, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, 
Kassouf W, Kiemeney LA, Vecchia C la, Shariat S, Lotan Y. Epidemiology 
and risk factors of urothelial bladder cancer. Eur Urol 2013; 63(2):234-241.
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Barlow L, Westergren K, Holmberg L and Talbäck M. The completeness of 
the Swedish Cancer Register – a sample survey for year 1998. Acta 
Oncologica. 2009; 48: 27-33.
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Zeegers MPA, Tan FE, Dorant E, Brandt PA van den. The impact of 
characteristics of cigarette smoking on urinary tract cancer risk: a meta-
analysis of epidemiologic studies. Cancer 2000; 89(3):630-639.
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Wideroff L, Gridley G, Mellemkjaer L et al. Cancer incidence in a population-
based cohort of patients hospitalized with diabetes mellitus in Denmark. J. 
Natl. Cancer Inst. 1997; 89: 1360-5.
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ENCePP. The ENCePP Code of Conduct for Scientific Independence and 
Transparency in the Conduct of Pharmacoepidemiological and 
Pharmacovigilance Studies. 21 November 2011, EMA/929209/2011. 
www.encepp.eu/code_of_conduct/documents/CodeofConduct_Rev2.pdf
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Teppo L, Pukkala E and Lehtonen M. Data quality and quality control of a 
population-based cancer registry. Acta Oncologica. 1994; 33: 365-369.
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NORDCAN Register [Internet]. Association of the Nordic Cancer Registries 
[cited 2015 June 18]. Available from: http://www-
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Herrett et al. Data Resource Profile: Clinical Practice Research Datalink 
(CPRD). Int J Epidemiol. 2015 44:827-36.
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Murchie P, Campbell NC, Delaney EK, Dinant GJ, Hannaford PC et al. 
Comparing Diagnostic delay in Cancer: a cross-sectional study in three 
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2012 29: 69-78.
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Boehringer Ingelheim International GmbH. Synjardy (empagliflozin, 
metformin hydrochloride) Summary of Product Characteristics.  Available at:  
https://www.ema.europa.eu/en/documents/product-information/synjardy-epar-
product-information_en.pdf. Accessed 21 August 2019
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Wolf et al. Data resource profile: Clinical Practice Research Datalink (CPRD) 
Aurum. Int J Epidemiol. 2019 Mar 11. pii: dyz034.
R19-2814
Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman 
MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, 
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Langkilde AM, Sabatine MS. Dapagliflozin and Cardiovascular Outcomes in 
Type 2 Diabetes. N Engl J Med 2019;380:347–357.

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R19-2928 
CPRD linked data [Internet, page last reviewed 8 August 2019]. Clinical 
Practice Research Datalink [cited 2019 Aug 21]. Available from: 
https://www.cprd.com/linked-data
12.2
UNPUBLISHSED REFERENCES
Not Applicable

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13.
ANNEXURE
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Number
Document 
number
Date
Title
1
c27031418-01
08 June 2021
Post-authorisation safety study to assess 
the risk of urinary tract malignancies in 
relation to empagliflozin exposure in 
patients with type 2 diabetes: a multi-
database European study – Fifth
monitoring interim report

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS

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ANNEX 3. READ CODES TO IDENTIFY TYPE 2 DIABETES
The codes will be updated for the data application.
Read code
Description
9OL..00
Diabetes monitoring admin
66A..00
Diabetic monitoring
66AS.00
Diabetic annual review
C10..00
Diabetes mellitus
9N1Q.00
Seen in diabetic clinic
C10F.00
Type 2 diabetes mellitus
9OL4.00
Diabetes monitoring 1st letter
66A2.00
Follow-up diabetic assessment
9NND.00
Under care of diabetic foot screener
66AP.00
Diabetes: practice programme
9OL1.00
Attends diabetes monitoring
66A4.00
Diabetic on oral treatment
68A7.00
Diabetic retinopathy screening
66AZ.00
Diabetic monitoring NOS
66AJ.00
Diabetic - poor control
C100112
Non-insulin dependent diabetes mellitus
66Ac.00
Diabetic peripheral neuropathy screening
9OL5.00
Diabetes monitoring 2nd letter
66A3.00
Diabetic on diet only
66Aq.00
Diabetic foot screen
C109.00
Non-insulin dependent diabetes mellitus
F420.00
Diabetic retinopathy
13B1.00
Diabetic diet
9OLA.00
Diabetes monitor. check done
7L19800
Subcutaneous injection of insulin
66AR.00
Diabetes management plan given
9h42.00
Excepted from diabetes quality indicators: Informed dissent
2G5E.00
O/E - Right diabetic foot at low risk
66A5.00
Diabetic on insulin

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Read code
Description
2G5I.00
O/E - Left diabetic foot at low risk
9h41.00
Excepted from diabetes qual indicators: Patient unsuitable
F420000
Background diabetic retinopathy
9N4I.00
DNA - Did not attend diabetic clinic
66AI.00
Diabetic - good control
C109.12
Type 2 diabetes mellitus
66AQ.00
Diabetes: shared care programme
66AD.00
Fundoscopy - diabetic check
8BL2.00
Patient on maximal tolerated therapy for diabetes
1434.00
H/O: diabetes mellitus
9OL6.00
Diabetes monitoring 3rd letter
66Ai.00
Diabetic 6 month review
9N1v.00
Seen in diabetic eye clinic
8CA4100
Pt advised re diabetic diet
2BBP.00
O/E - right eye background diabetic retinopathy
2BBQ.00
O/E - left eye background diabetic retinopathy
8B3l.00
Diabetes medication review
66A9.00
Understands diet - diabetes
66Ab.00
Diabetic foot examination
42W..00
Hb. A1C - diabetic control
66AU.00
Diabetes care by hospital only
9NM0.00
Attending diabetes clinic
8H7r.00
Refer to diabetic foot screener
8I3X.00
Diabetic retinopathy screening refused
2G5F.00
O/E - Right diabetic foot at moderate risk
2G5J.00
O/E - Left diabetic foot at moderate risk
66A1.00
Initial diabetic assessment
F420400
Diabetic maculopathy
66AW.00
Diabetic foot risk assessment
9OLA.11
Diabetes monitored
13AB.00
Diabetic lipid lowering diet

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Read code
Description
2BBM.00
O/E - diabetic maculopathy absent both eyes
ZC2C800
Dietary advice for diabetes mellitus
C100100
Diabetes mellitus, adult onset, no mention of complication
66Ao.00
Diabetes type 2 review
9OL8.00
Diabetes monitor.phone invite
9N4p.00
Did not attend diabetic retinopathy clinic
9N1i.00
Seen in diabetic foot clinic
14P3.00
H/O: insulin therapy
C101.00
Diabetes mellitus with ketoacidosis
66A8.00
Has seen dietician - diabetes
66AT.00
Annual diabetic blood test
C10FJ00
Insulin treated Type 2 diabetes mellitus
9OL3.00
Diabetes monitoring default
66AV.00
Diabetic on insulin and oral treatment
66A7.00
Frequency of hypo. attacks
9OL..11
Diabetes clinic administration
66AA.11
Injection sites - diabetic
66AH000
Conversion to insulin
8CS0.00
Diabetes care plan agreed
2G5G.00
O/E - Right diabetic foot at high risk
66AH.00
Diabetic treatment changed
2G5K.00
O/E - Left diabetic foot at high risk
9OLD.00
Diabetic patient unsuitable for digital retinal photography
F372.12
Diabetic neuropathy
F420600
Non-proliferative diabetic retinopathy
C106.12
Diabetes mellitus with neuropathy
9OL7.00
Diabetes monitor. verbal invite
C106.00
Diabetes mellitus with neurological manifestation
8H4F.00
Referral to diabetologist
8I3W.00
Diabetic foot examination declined
68A9.00
Diabetic retinopathy screening offered

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Description
13AC.00
Diabetic weight reducing diet
F420100
Proliferative diabetic retinopathy
66AY.00
Diabetic diet - good compliance
C10FM00
Type 2 diabetes mellitus with persistent microalbuminuria
C109.13
Type II diabetes mellitus
C109.11
NIDDM - Non-insulin dependent diabetes mellitus
9OLZ.00
Diabetes monitoring admin.NOS
2G5A.00
O/E - Right diabetic foot at risk
2BBW.00
O/E - right eye diabetic maculopathy
2BBX.00
O/E - left eye diabetic maculopathy
2G5B.00
O/E - Left diabetic foot at risk
8HBG.00
Diabetic retinopathy 12 month review
8H7C.00
Refer, diabetic liaison nurse
C109J00
Insulin treated Type 2 diabetes mellitus
66Af.00
Patient diabetes education review
66A6.00
Last hypo. attack
ZLA2500
Seen by diabetic liaison nurse
8Hj0.00
Referral to diabetes structured education programme
7276.00
Pan retinal photocoagulation for diabetes
C10FL00
Type 2 diabetes mellitus with persistent proteinuria
8Hl1.00
Referral for diabetic retinopathy screening
68AB.00
Diabetic digital retinopathy screening offered
8Hj4.00
Referral to DESMOND diabetes structured education programme
F420200
Preproliferative diabetic retinopathy
C104.11
Diabetic nephropathy
8HTk.00
Referral to diabetic eye clinic
9h4..00
Exception reporting: diabetes quality indicators
C100.00
Diabetes mellitus with no mention of complication
2BBL.00
O/E - diabetic maculopathy present both eyes
66AM.00
Diabetic - follow-up default
9N2i.00
Seen by diabetic liaison nurse

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Description
C10F.11
Type II diabetes mellitus
M271200
Mixed diabetic ulcer - foot
2BBR.00
O/E - right eye preproliferative diabetic retinopathy
66Ae.00
HbA1c target
2BBS.00
O/E - left eye preproliferative diabetic retinopathy
8H7f.00
Referral to diabetes nurse
42c..00
HbA1 - diabetic control
M271000
Ischaemic ulcer diabetic foot
679R.00
Patient offered diabetes structured education programme
F171100
Autonomic neuropathy due to diabetes
66Am.00
Insulin dose changed
ZL62500
Referral to diabetes nurse
C109700
Non-insulin dependent diabetes mellitus - poor control
F464000
Diabetic cataract
F420z00
Diabetic retinopathy NOS
C10FC00
Type 2 diabetes mellitus with nephropathy
C105.00
Diabetes mellitus with ophthalmic manifestation
8Hj5.00
Referral to XPERT diabetes structured education programme
2BBT.00
O/E - right eye proliferative diabetic retinopathy
C10F600
Type 2 diabetes mellitus with retinopathy
M271100
Neuropathic diabetic ulcer - foot
8Hl4.00
Referral to community diabetes specialist nurse
2BBV.00
O/E - left eye proliferative diabetic retinopathy
C104.00
Diabetes mellitus with renal manifestation
9N0m.00
Seen in diabetic nurse consultant clinic
9OLB.00
Attended diabetes structured education programme
9NN9.00
Under care of diabetes specialist nurse
66Aa.00
Diabetic diet - poor compliance
C107.00
Diabetes mellitus with peripheral circulatory disorder
F372.00
Polyneuropathy in diabetes
66AJz00
Diabetic - poor control NOS

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Description
9N2d.00
Seen by diabetologist
8H2J.00
Admit diabetic emergency
2BBF.00
Retinal abnormality - diabetes related
9OL2.00
Refuses diabetes monitoring
66Ad.00
Hypoglycaemic attack requiring 3rd party assistance
8A13.00
Diabetic stabilisation
C10F700
Type 2 diabetes mellitus - poor control
9N0n.00
Seen in community diabetes specialist clinic
93C4.00
Patient consent given for addition to diabetic register
66AJ.11
Unstable diabetes
9M00.00
Informed consent for diabetes national audit
F420300
Advanced diabetic maculopathy
C10F900
Type 2 diabetes mellitus without complication
66AJ000
Chronic hyperglycaemia
66AK.00
Diabetic - cooperative patient
2G5C.00
Foot abnormality - diabetes related
66Ap.00
Insulin treatment initiated
9N0o.00
Seen in community diabetic specialist nurse clinic
9NN8.00
Under care of diabetologist
ZL62600
Referral to diabetic liaison nurse
C100z00
Diabetes mellitus NOS with no mention of complication
N030100
Diabetic Charcot arthropathy
F381311
Diabetic amyotrophy
TJ23A00
Adverse reaction to metformin hydrochloride
M037200
Cellulitis in diabetic foot
C10FN00
Type 2 diabetes mellitus with ketoacidosis
66AN.00
Date diabetic treatment start
8HHy.00
Referral to diabetic register
2G5H.00
O/E - Right diabetic foot - ulcerated
2G51000
Foot abnormality - diabetes related
2G5L.00
O/E - Left diabetic foot - ulcerated

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Description
66Ak.00
Diabetic monitoring - lower risk albumin excretion
9OLM.00
Diabetes structured education programme declined
8CR2.00
Diabetes clinical management plan

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Description
C10FK00
Hyperosmolar non-ketotic state in type 2 diabetes mellitus
66A7100
Frequency of GP or paramedic treated hypoglycaemia
ZV65312
Dietary counselling in diabetes mellitus
C103.00
Diabetes mellitus with ketoacidotic coma
ZRB6.00
Diabetes wellbeing questionnaire
66AJ200
Loss of hypoglycaemic warning
9OLK.00
DESMOND diabetes structured education programme completed
C104z00
Diabetes mellitus with nephropathy NOS
F372100
Chronic painful diabetic neuropathy
F3y0.00
Diabetic mononeuropathy
C107.11
Diabetes mellitus with gangrene
F372.11
Diabetic polyneuropathy
66AL.00
Diabetic-uncooperative patient
9kL..00
Insulin initiation - enhanced services administration
9OLL.00
XPERT diabetes structured education programme completed
C109400
Non-insulin dependent diabetes mellitus with ulcer
C10D.00
Diabetes mellitus autosomal dominant type 2
M21yC00
Insulin lipohypertrophy
L180500
Pre-existing diabetes mellitus, insulin-dependent
C109900
Non-insulin-dependent diabetes mellitus without complication
66A7000
Frequency of hospital treated hypoglycaemia
8H4e.00
Referral to diabetes special interest general practitioner
C106z00
Diabetes mellitus NOS with neurological manifestation
C102.00
Diabetes mellitus with hyperosmolar coma
K01x100
Nephrotic syndrome in diabetes mellitus
66AJ300
Recurrent severe hypos
C101z00
Diabetes mellitus NOS with ketoacidosis
G73y000
Diabetic peripheral angiopathy
66Al.00
Diabetic monitoring - higher risk albumin excretion
ZRbH.00
Perceived control of insulin-dependent diabetes
N030000
Diabetic cheiroarthropathy

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Read code
Description
8A12.00
Diabetic crisis monitoring
C105z00
Diabetes mellitus NOS with ophthalmic manifestation
9OLN.00
Diabetes monitor invitation by SMS (short message service)
8HBH.00
Diabetic retinopathy 6 month review
ZL22500
Under care of diabetic liaison nurse
9OLF.00
Diabetes structured education programme completed
F35z000
Diabetic mononeuritis NOS
8H3O.00
Non-urgent diabetic admission
C10FQ00
Type 2 diabetes mellitus with exudative maculopathy
C10G.00
Secondary pancreatic diabetes mellitus
C10F000
Type 2 diabetes mellitus with renal complications
C10F911
Type II diabetes mellitus without complication
C106100
Diabetes mellitus, adult onset, + neurological manifestation
C10FB00
Type 2 diabetes mellitus with polyneuropathy
C10F200
Type 2 diabetes mellitus with neurological complications
7L10000
Continuous subcutaneous infusion of insulin
66AG.00
Diabetic drug side effects
8HLE.00
Diabetology D.V. done
C10FH00
Type 2 diabetes mellitus with neuropathic arthropathy
F372200
Asymptomatic diabetic neuropathy
9OLG.00
Attended XPERT diabetes structured education programme
C109600
Non-insulin-dependent diabetes mellitus with retinopathy
U60231C
Adverse reaction to metformin hydrochloride
8Hg4.00
Discharged from care of diabetes specialist nurse
F420500
Advanced diabetic retinal disease
9OL9.00
Diabetes monitoring deleted
M21yC11
Insulin site lipohypertrophy
C10FE00
Type 2 diabetes mellitus with diabetic cataract
2BBk.00
O/E - right eye stable treated prolif diabetic retinopathy
F372000
Acute painful diabetic neuropathy
66AO.00
Date diabetic treatment stopp

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Description
TJ23400
Adverse reaction to gliclazide
8I3k.00
Insulin therapy declined
C105100
Diabetes mellitus, adult onset, + ophthalmic manifestation
Cyu2.00
Diabetes mellitus
9OLJ.00
DAFNE diabetes structured education programme completed
C107.12
Diabetes with gangrene
C10zz00
Diabetes mellitus NOS with unspecified complication
44V3.00
Glucose tol. test diabetic
C10F400
Type 2 diabetes mellitus with ulcer
C10FJ11
Insulin treated Type II diabetes mellitus
42WZ.00
Hb. A1C - diabetic control NOS
ZLD7500
Discharge by diabetic liaison nurse
C107z00
Diabetes mellitus NOS with peripheral circulatory disorder
C10K.00
Type A insulin resistance
C10A100
Malnutrition-related diabetes mellitus with ketoacidosis
ZV6DA00
Admitted for commencement of insulin
C101000
Diabetes mellitus, juvenile type, with ketoacidosis
2BBl.00
O/E - left eye stable treated prolif diabetic retinopathy
9OLH.00
Attended DAFNE diabetes structured education programme
C106.13
Diabetes mellitus with polyneuropathy
R054200
Gangrene of toe in diabetic
C10y.00
Diabetes mellitus with other specified manifestation
C10F711
Type II diabetes mellitus - poor control
C10FL11
Type II diabetes mellitus with persistent proteinuria
U602300
Insul/oral hypoglyc drugs caus adverse eff therapeut use
C10z.00
Diabetes mellitus with unspecified complication
C109C00
Non-insulin dependent diabetes mellitus with nephropathy
C10F100
Type 2 diabetes mellitus with ophthalmic complications
679L000
Education in self-management of diabetes
C10z100
Diabetes mellitus, adult onset, + unspecified complication
C10FR00
Type 2 diabetes mellitus with gastroparesis

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Description
8Hj3.00
Referral to DAFNE diabetes structured education programme
C10FA00
Type 2 diabetes mellitus with mononeuropathy
C10FD00
Type 2 diabetes mellitus with hypoglycaemic coma
2G5W.00
O/E - left chronic diabetic foot ulcer
F440700
Diabetic iritis
ZC2CA00
Dietary advice for type II diabetes
C10A.00
Malnutrition-related diabetes mellitus
C10N.00
Secondary diabetes mellitus
R054300
[D]Widespread diabetic foot gangrene
C104100
Diabetes mellitus, adult onset, with renal manifestation
C10N100
Cystic fibrosis related diabetes mellitus
F345000
Diabetic mononeuritis multiplex
C109711
Type II diabetes mellitus - poor control
C107200
Diabetes mellitus, adult with gangrene
C10F500
Type 2 diabetes mellitus with gangrene
2BBo.00
O/E - sight threatening diabetic retinopathy
C101100
Diabetes mellitus, adult onset, with ketoacidosis
C109712
Type 2 diabetes mellitus - poor control
C107100
Diabetes mellitus, adult, + peripheral circulatory disorder
8HVU.00
Private referral to diabetologist
C109J12
Insulin treated Type II diabetes mellitus
F381300
Myasthenic syndrome due to diabetic amyotrophy
ZV6DB00
Admitted for conversion to insulin
8HTi.00
Referral to multidisciplinary diabetic clinic
66Ae000
HbA1c target level - IFCC standardised
TJ23000
Adverse reaction to insulins
F420700
High risk proliferative diabetic retinopathy
C10F611
Type II diabetes mellitus with retinopathy
2G5V.00
O/E - right chronic diabetic foot ulcer
C109K00
Hyperosmolar non-ketotic state in type 2 diabetes mellitus
C102100
Diabetes mellitus, adult onset, with hyperosmolar coma

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Description
C10FF00
Type 2 diabetes mellitus with peripheral angiopathy
F420800
High-risk non-proliferative diabetic retinopathy
C107400
NIDDM with peripheral circulatory disorder
C10F300
Type 2 diabetes mellitus with multiple complications
8CP2.00
Transition of diabetes care options discussed
N030011
Diabetic cheiropathy
66At.00
Diabetic dietary review
C10M.00
Lipoatrophic diabetes mellitus
9M10.00
Informed dissent for diabetes national audit
C10FP00
Type 2 diabetes mellitus with ketoacidotic coma
C109611
Type II diabetes mellitus with retinopathy
C10FG00
Type 2 diabetes mellitus with arthropathy
C109J11
Insulin treated non-insulin dependent diabetes mellitus
C101y00
Other specified diabetes mellitus with ketoacidosis
C109411
Type II diabetes mellitus with ulcer
8I2S.00
Glitazones contraindicated
C109000
Non-insulin-dependent diabetes mellitus with renal comps
C109100
Non-insulin-dependent diabetes mellitus with ophthalm comps
C106y00
Other specified diabetes mellitus with neurological comps
TJ23.00
Adverse reaction to insulins and antidiabetic agents
9h43.00
Excepted from diabetes qual indicators: service unavailable
C106.11
Diabetic amyotrophy
TJ23z00
Adverse reaction to insulins and antidiabetic agents NOS
C104y00
Other specified diabetes mellitus with renal complications
C109612
Type 2 diabetes mellitus with retinopathy
C109212
Type 2 diabetes mellitus with neurological complications
C109200
Non-insulin-dependent diabetes mellitus with neuro comps
C106000
Diabetes mellitus, juvenile, + neurological manifestation
ZRB4.00
Diabetes clinic satisfaction questionnaire
C109412
Type 2 diabetes mellitus with ulcer
ZRB5.11
DTSQ - Diabetes treatment satisfaction questionnaire

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Description
C109E00
Non-insulin depend diabetes mellitus with diabetic cataract
8I2P.00
Sulphonylureas contraindicated
C109B00
Non-insulin dependent diabetes mellitus with polyneuropathy
C109E11
Type II diabetes mellitus with diabetic cataract
8HKE.00
Diabetology D.V. requested
C10yz00
Diabetes mellitus NOS with other specified manifestation
C109C12
Type 2 diabetes mellitus with nephropathy
C109500
Non-insulin dependent diabetes mellitus with gangrene
C109H00
Non-insulin dependent d m with neuropathic arthropathy
C109D00
Non-insulin dependent diabetes mellitus with hypoglyca coma
C109011
Type II diabetes mellitus with renal complications
C109300
Non-insulin-dependent diabetes mellitus with multiple comps
U602312
Adverse reaction to insulins
C10zy00
Other specified diabetes mellitus with unspecified comps
U602311
Adverse reaction to insulins and antidiabetic agents
TJ23500
Adverse reaction to glipizide
66Ar.00
Insulin treatment stopped
C109H11
Type II diabetes mellitus with neuropathic arthropathy
889A.00
Diab mellit insulin-glucose infus acute myocardial infarct
C109H12
Type 2 diabetes mellitus with neuropathic arthropathy
9NiC.00
Did not attend DAFNE diabetes structured education programme
66AQ100
Declined consent for diabetes year of care programme
C10yy00
Other specified diabetes mellitus with other spec comps
C10F311
Type II diabetes mellitus with multiple complications
C109E12
Type 2 diabetes mellitus with diabetic cataract
C108y00
Other specified diabetes mellitus with multiple comps
TJ23300
Adverse reaction to glibenclamide
C109511
Type II diabetes mellitus with gangrene
C10y100
Diabetes mellitus, adult, + other specified manifestation
C10N000
Secondary diabetes mellitus without complication
66As.00
Diabetic on subcutaneous treatment

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Description
66At100
Type II diabetic dietary review
C109012
Type 2 diabetes mellitus with renal complications
C109D12
Type 2 diabetes mellitus with hypoglycaemic coma
U602316
Adverse reaction to gliclazide
C102z00
Diabetes mellitus NOS with hyperosmolar coma
C109512
Type 2 diabetes mellitus with gangrene
C109F00
Non-insulin-dependent d m with peripheral angiopath
C109C11
Type II diabetes mellitus with nephropathy
C103z00
Diabetes mellitus NOS with ketoacidotic coma
9N1o.00
Seen in multidisciplinary diabetic clinic
C109G00
Non-insulin dependent diabetes mellitus with arthropathy
C105y00
Other specified diabetes mellitus with ophthalmic complicatn
C109F11
Type II diabetes mellitus with peripheral angiopathy
C10FM11
Type II diabetes mellitus with persistent microalbuminuria
C10F411
Type II diabetes mellitus with ulcer
66Au.00
Diabetic erectile dysfunction review
66Av.00
Diabetic assessment of erectile dysfunction
Cyu2000
Other specified diabetes mellitus
C109B11
Type II diabetes mellitus with polyneuropathy
C10F011
Type II diabetes mellitus with renal complications
C103y00
Other specified diabetes mellitus with coma
C109211
Type II diabetes mellitus with neurological complications
ZRB4.11
CSQ - Diabetes clinic satisfaction questionnaire
3883.00
Diabetes treatment satisfaction questionnaire
8IAs.00
Diabetic dietary review declined
2BBr.00
Impaired vision due to diabetic retinopathy
TJ23900
Adverse reaction to tolbutamide
C10FB11
Type II diabetes mellitus with polyneuropathy
C109D11
Type II diabetes mellitus with hypoglycaemic coma
C109111
Type II diabetes mellitus with ophthalmic complications
C109F12
Type 2 diabetes mellitus with peripheral angiopathy

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Description
C10A000
Malnutrition-related diabetes mellitus with coma
C103100
Diabetes mellitus, adult onset, with ketoacidotic coma
C109A00
Non-insulin dependent diabetes mellitus with mononeuropathy
8HME.00
Listed for Diabetology admissn
C10FA11
Type II diabetes mellitus with mononeuropathy
U60231B
Adverse reaction to tolbutamide
U60231E
Adverse reaction to insulins and antidiabetic agents NOS
Cyu2300
Unspecified diabetes mellitus with renal complications
8HgC.00
Discharged from diabetes shared care programme
66AQ000
Unsuitable for diabetes year of care programme
C10F111
Type II diabetes mellitus with ophthalmic complications
TJ23B00
Adverse reaction to glucagon
C109G11
Type II diabetes mellitus with arthropathy
U602315
Adverse reaction to glibenclamide
C109G12
Type 2 diabetes mellitus with arthropathy
C109A11
Type II diabetes mellitus with mononeuropathy
C10K000
Type A insulin resistance without complication
U60231A
Adverse reaction to tolazamide
C108z00
Unspecified diabetes mellitus with multiple complications
C109112
Type 2 diabetes mellitus with ophthalmic complications
U602318
Adverse reaction to gliquidone
TJ23200
Adverse reaction to chlorpropamide
C10FE11
Type II diabetes mellitus with diabetic cataract
U602317
Adverse reaction to glipzide
C10G000
Secondary pancreatic diabetes mellitus without complication
ZRB6.11
DWBQ - Diabetes wellbeing questionnaire
C10F211
Type II diabetes mellitus with neurological complications
C10E512
Insulin-dependent diabetes mellitus with ulcer
C10FD11
Type II diabetes mellitus with hypoglycaemic coma
SL23100
Biguanide poisoning
Kyu0300
Glomerular disorders in diabetes mellitus

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Description
C10A500
Malnutritn-relat diabetes melitus wth periph circul complctn
C10FC11
Type II diabetes mellitus with nephropathy
66Aw.00
Insulin dose
TJ23800
Adverse reaction to tolazamide

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ANNEX 4. CODES TO IDENTIFY EXPOSURE VARIABLES
No.
Variable
ATC codes3
Time-dependent
(T) / fixed at 
cohort entry (F)
How the effect of 
variable is 
accounted for1
1
AT / ITT: Empagliflozin
Empagliflozin
A10BK03 (current), 
A10BX12
(previous)
DPP-4 inhibitors
ATC beginning 
with A10BH
Fixed-dose 
combinations 
Will be identified 
from ATC class 
A10BD
T / F
E
2
AT / ITT: DPP-4 inhibitor
T / F
E
3
AT / ITT, FDCM2: 
empagliflozin
T / F
E
4
AT / ITT, FDCM2: DPP-4 
inhibitor
T / F
E
5
Empagliflozin current use
T
E
6
Empagliflozin: cumulative 
duration of exposure
T
E
7
Empagliflozin: cumulative 
dosage of exposure
T
E
8
Empagliflozin: time since 
last dose
T
E
Other OAD treatments
9
Metformin
ATC beginning 
with A10BA
T
PS / A / VS, RS, 
TV, SG
10
Sulphonylureas
ATC beginning 
with A10BB
T
PS / A / VS, RS, 
TV

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No.
Variable
ATC codes3
Time-dependent
(T) / fixed at 
cohort entry (F)
How the effect of 
variable is 
accounted for1
11
Insulin
ATC beginning 
with A10A
T
PS / A / VS, RS, 
TV
12
Thiazolidinediones
ATC beginning 
with A10BG
T
PS / A / VS, RS, 
TV
13
Alpha glucosidase 
inhibitors
ATC beginning 
with A10BF
T
PS / A / VS, RS, 
TV
14
GLP-1 agonists
Will be identified 
from ATC classes 
A10BJ and A10BX
T
PS / A / VS, RS, 
TV
15
Other blood glucose 
lowering drugs, excluding 
insulins
ATC beginning 
with A10BX that is 
not included 
elsewhere
16
Treatment complexity 
(mono, dual and triple 
combination therapy)
T
PS / A / VS, RS, 
TV
17
Switch or add-on
T
PS / A / VS, RS, 
TV
Exclusion / Censoring
18
DPP-4 (Linagliptin) and 
Empagliflozin
A10BD19
T
Censoring / 
Exclusion
19
Discontinuation of primary 
exposure
T
Censoring
20
Switch to other SGLT-2 
inhibitor use
A10BK02, 
A10BX11, 
A10BK01, 
A10BX09, 
A10BK04, 
A10BD16, 
A10BD15, 
A10BD23
T
Censoring / 
Exclusion

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No.
Variable
ATC codes3
Time-dependent
(T) / fixed at 
cohort entry (F)
How the effect of 
variable is 
accounted for1
21
Use of fixed-dose 
combinations of SGLT-2 
inhibitors with DPP-4 
inhibitors
Identified from 
ATC class A10BD
T
Censoring / 
Exclusion
1 E – Exposure, A – adjusted in the Cox model, VS – potential confounder and will be adjusted for using variable selection, 
PS – one of the PS matching variable at baseline, TV – time-varying confounder and adjusted for in MSM, RS –
defines the risk set in NCC, SG – used as a subgroup in stratified analyses,  / - and/or
2 FDCM – Fixed-dose combination with metformin
3 New drugs will be included in the variable definitions if they become available during the study period. 

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ANNEX 5. CODES TO IDENTIFY THE OUTCOME VARIABLES
The codes will be updated for the data applications.
No.
Variable
ICD-10 / ICD-
O-3 codes
READ 
codes
Outcome 
/ 
Censoring 
variable
Analyses1
1
Urinary Tract cancer 
(malignant 
and 
carcinoma in situ)
C64-C68
D09.0, D09.1
Byu9, B837, 
B83z, B4A, 
B49
Outcome
D, P, S, F , 
NCC, MSM 
Sens
2
Bladder 
cancer 
(malignant 
and 
carcinoma in situ)
C67, D09.0
B49, B837, 
selected 
BB4 codes
Outcome
D, P, S, F , 
Sens
3
Renal 
cancer 
(malignant)
C64, C65
B4A0, B4A1
Outcome
D, P, S, F , 
Sens
4
Other 
urinary 
tract 
cancer 
(non-renal, 
non-bladder cancers) –
sensitivity (malignant)
C66,C68
Byu9
Sensitivity 
outcome
D, Sens
5
Urinary Tract cancers 
from GP data (CPRD 
only) – sensitivity
Byu9, B837, 
B83z, B4A, 
B49
Sensitivity 
outcome
Sens
6
Urinary 
tract 
neoplasms of uncertain 
or unknown behaviour 
- sensitivity
D41
B917, B91z, 
BA04
Sensitivity 
outcome
Sens
Censoring variables
7
Other non-UT cancers
C00-C99, D00-
09 (excl. C64-
68, 
D09.0, 
D09.1)
B 
(excl. 
Byu9, B837, 
B83z, B4A, 
B49, 
B49, 
B837, 
selected 
BB4 codes)
Censoring
8
End of study period
Censoring
9
End of GP practice 
coverage
Censoring
10
Use of other SGLT-2 
(since start of follow-
up)
Censoring
11
Use 
of 
fixed-dose 
combinations 
of 
Censoring

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No.
Variable
ICD-10 / ICD-
O-3 codes
READ 
codes
Outcome 
/ 
Censoring 
variable
Analyses1
SGLT-2 
inhibitors 
with DPP-4 inhibitors
12
Patient transfer
Censoring
13
End stage renal disease 
/ renal dialysis
Censoring
14
All-cause 
mortality 
(excluding UT cancer 
mortality)
Censoring
15
Discontinuation 
of 
primary exposure
Censoring 
for 
as-treated 
analysis
16
UT 
cancer 
characteristics
(based 
on 
staging, 
TNM codes, etc)
Sensitivity 
outcome 
/ 
descriptive
D, Sens
1 D=Descriptive, P =Primary , S = secondary, F = further, Sens = sensitivity, NCC =Nested-case-control, MSM – marginal 
structural models

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ANNEX 6. COVARIATES TO BE CONSIDERED FOR INCLUSION IN 
THE PROPENSITY SCORE MODEL. 
No.
Variable
Socio-demographic variables
1
Age 
2
Sex
3
Socioeconomic status
4
Calendar year of index date
5
Duration of look-back period
6
Duration of treated diabetes at index date
Diabetic complications
7
Diabetic retinopathy or diabetic maculopathy
8
Diabetic nephropathy
9
Diabetic neuropathy
10
Peripheral vascular disease
11
Diabetic lower limb severe complications
Urinary tract related comorbidities
12
Kidney or genitourinary stones
13
Prior history of UTI or pyelonephritis
14
Liver disease
15
eGFR
16
Renal impairment
17
Prior ICU admission
18
Pancreatitis

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19
BMI (when available)
20
Smoking (when available)
21
Alcohol use (when available)
22
HbA1c (when available)
23
Albuminuria testing 
Cardiovascular Diseases 
24
Congestive heart failure
25
Blood pressure measurements
26
Hypertension
27
Stroke
28
Myocardial infarction
29
Autoimmune disease
30
COPD
31
Time since first diabetes diagnosis
Other non-diabetes medications
32
Antihypertensives/diuretics
33
Non-steroidal anti-inflammatory drugs (NSAIDs)
34
Oral steroids
35
Statins, fibrates
36
Lipid modifying agents
37
Zoledronic acid
38
Antibiotics
39
Other drugs
BMI=body mass index; COPD=chronic obstructive pulmonary disease; eGFR=estimated glomerular filtration rate; 
HbA1c=glycated haemoglobin A1c; HF=heart failure; ICU=intensive care unit; MSM=marginal structural model; 
NCC=nested case-control; PS=propensity score; UTI=urinary tract infection.

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SIGNATURE

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
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Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03856813
11.0
1245-0097-clinical-trial-protocol
Post-authorisation safety study to assess the risk of urinary tract malignancies in
relation to empagliflozin exposure in patients with type 2 diabetes: a multi-database
European study
Approval-EU Qualified Person
Pharmacovigilance
15 Jun 2023 14:04 CEST
Verification-Paper Signature
Completion
15 Jun 2023 14:13 CEST
Approval
15 Jun 2023 15:02 CEST
Approval-On behalf of 
 or VP
or 
15 Jun 2023 15:21 CEST
Approval
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Approval-Team Member Drug
Safety
19 Jun 2023 17:28 CEST

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