Multi-country Non-interventional Study on the Effectiveness of Empagliflozin in Adult Patients With Type 2 Diabetes in Europe and Asia.
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-124_RD-01 (4.0)
e  title PAGE
Protocol for non-interventional studies based on existing data
TITLE PAGE
Document Number:
c26457869-02
BI Study Number:
1245.195
BI Investigational
Product(s):
Jardiance ® (empagliflozin)
Title:
Multi-country non-interventional study on the effectiveness
and safety of Empagliflozin in adult patients with type 2 
diabetes in Europe and Asia
Protocol version 
identifier:
2.0
Date of the last version 
of the protocol:
29 November 2018
PASS:
No
EU PAS register 
number:
EUPAS27606
Active substance:
A10BK03 empagliflozin
Medicinal product:
Jardiance
Product reference:
Europe: EMEA/H/C/002677
Asia: NA
Procedure number:
N/A
Joint PASS:
No
Research question and 
objectives:
The main objective of this study is to compare effectiveness 
outcomes between the incident users of empagliflozin or any 
SGLT-2 inhibitor and the incident users of any DPP-4 
inhibitor. The effectiveness outcomes include, where available,
cardiovascular events, renal effectiveness outcomes, and 
cardiovascular and all-cause mortality. Additional analyses 
include safety outcomes. Health care resources utilization and 
cost of care outcomes will also be evaluated.
Countries of study:
Denmark, Finland, Germany, Israel, Japan, Norway, South 
Korea, Spain, Sweden, Taiwan, United Kingdom. Other
countries may be included later.

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001-MCS-90-124_RD-01 (4.0)
Author:
 
 
Marketing 
authorization holder:
MAH contact person:
In case of PASS, add:
<EU-QPPV:>
N/A
In case of PASS, add:
<Signature of EU-
QPPV:>
N/A
Date:
11 October 2019
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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1.
TABLE OF CONTENTS
TITLE PAGE.............................................................................................................................1
1.
TABLE OF CONTENTS........................................................................................3
2.
LIST OF ABBREVIATIONS.................................................................................6
3.
RESPONSIBLE PARTIES.....................................................................................7
4.
ABSTRACT..........................................................................................................10
5.
AMENDMENTS AND UPDATES......................................................................15
6.
MILESTONES......................................................................................................16
7.
RATIONALE AND BACKGROUND.................................................................16
8.
RESEARCH QUESTION AND OBJECTIVES...................................................19
8.1
PRIMARY OBJECTIVES: EFFECTIVENESS............................................19
8.2
SECONDARY OBJECTIVES ON CARDIOVASCULAR 
EFFECTIVENESS.........................................................................................20
8.3
SECONDARY OBJECTIVES ON RENAL EFFECTIVENESS..................20
8.4
SECONDARY OBJECTIVES ON SAFETY................................................20
8.5
SECONDARY OBJECTIVES ON HEALTH CARE RESOURCE 
UTILIZATION (HCRU) AND COST OF CARE.........................................21
9.
RESEARCH METHODS .....................................................................................22
9.1
STUDY DESIGN...........................................................................................22
9.1.1
Country-specific studies as components of this multi-country study............23
9.2
SETTING.......................................................................................................24
9.2.1
Overview........................................................................................................24
9.2.2
Study population............................................................................................26
9.2.3
Study period and follow-up ...........................................................................28
9.3
VARIABLES .................................................................................................28
9.3.1
Exposures: study drugs ..................................................................................29
9.3.2
Outcomes .......................................................................................................35
9.3.3
Covariates at baseline (baseline characteristics)............................................41
9.4
DATA SOURCES .........................................................................................42
9.5
STUDY SIZE.................................................................................................42

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9.6
DATA MANAGEMENT...............................................................................45
9.6.1
Country-specific studies.................................................................................45
9.6.2
A multi-country study combining country-specific results ...........................45
9.7
DATA ANALYSIS........................................................................................46
9.7.1
Propensity score methodology.......................................................................46
9.7.2
Baseline characteristics / descriptive statistics ..............................................47
9.7.3
Primary effectiveness outcomes ....................................................................51
9.7.5
Secondary outcomes: effectiveness, safety, HCRU and costs of care...........54
 
9.7.7
Combining effectiveness results from countries: meta-analyses...................62
9.7.8
Presenting the HCRU and cost of care results from countries descriptively.63
9.7.9
Adjustment for multiple comparisons............................................................63
9.8
QUALITY CONTROL..................................................................................63
9.8.1
Country-specific studies: localized protocols, localized SAPs, country-
specific analyses, and country-specific study reports....................................63
9.8.2
Multi-country study: master protocol, master SAP, analyses with aggregate-
level results from the countries, and final report ...........................................63
9.9
LIMITATIONS OF THE RESEARCH METHODS.....................................64
9.9.1
Data sources and variables.............................................................................64
9.9.2
Identifying patients with T2DM ....................................................................65
9.9.3
Drug exposure................................................................................................65
9.9.4
Bias and confounding ....................................................................................65
9.9.5
Analyses.........................................................................................................65
9.10
OTHER ASPECTS........................................................................................65
9.11
SUBJECTS ....................................................................................................65
9.11.1
Cases ..............................................................................................................65
9.11.2
Controls..........................................................................................................65
9.12
BIAS ..............................................................................................................66
10.
PROTECTION OF HUMAN SUBJECTS ...........................................................66
10.1
COUNTRY-SPECIFIC STUDIES ................................................................66

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10.2
MULTI-COUNTRY STUDY........................................................................66
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ........................................................................................................66
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS .............................................................................................................67
13.
REFERENCES......................................................................................................68
13.1
PUBLISHED REFERENCES .......................................................................68
13.2
UNPUBLISHED REFERENCES..................................................................70
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.........................................................71
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .........................................72
ANNEX 3. REQUIREMENTS FOR THE LOCALIZED PROTOCOLS ..............................78
ANNEX 4. ALTERNATIVE DEFINITION OF EXPOSURE PERIODS (DRUG SUPPLY 
UNAVAILABLE).................................................................................................80
ANNEX 5. DEFINITIONS FOR INCLUSION AND EXCLUSION CRITERIA..................81
ANNEX 6. VARIABLE DEFINITIONS FOR OUTCOMES.................................................86
ANNEX 7. DEFINITIONS FOR COVARIATES AT BASELINE........................................97
ANNEX 8. DIAGNOSIS CODES FOR OTHER VARIABLES REQUIRED FOR 
ANALYSES........................................................................................................132

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2.
LIST OF ABBREVIATIONS
AT
As-treated
ATC
Anatomical Therapeutic Chemical classification 
BI
Boehringer Ingelheim International GmbH
BNP
B-type natriuretic peptide
BUN
Blood urea nitrogen
CABG
Coronary artery bypass grafting
CHF
Congestive heart failure
CI
Confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
COPD
Chronic obstructive pulmonary disease
CV
Cardiovascular
DPP-4
Dipeptidyl peptidase-4
eGFR
Estimated glomerular filtration rate
ENCePP
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance
ESRD
End-stage renal disease
GP
Grace period
HbA1c
Glycated hemoglobin A1c
HCRU
Healthcare resource utilization
HR
Hazard ratio
ICD-9
International Classification of Diseases, 9th revision
ICD-10
International Classification of Diseases, 10th revision
ITT
Intention to treat
KDIGO
Kidney Disease Improving Global Outcomes
MA
Marketing authorization
MACE
Major adverse cardiovascular event
MI
Myocardial infarction
NT
N-terminal
PS
Propensity score
PTCA
Percutaneous transluminal coronary angioplasty
SAP
Statistical analysis plan
SCr
Serum creatinine
SD
Standard deviation

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SGLT-2
Sodium-glucose cotransporter-2
STD.
Standardized difference
T1DM
Type 1 diabetes mellitus
T2DM
Type 2 diabetes mellitus
3.
RESPONSIBLE PARTIES
Global Principal Investigators
Local Principal Investigators and Participating Institutions 

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Sponsor
Boehringer Ingelheim International GmbH

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In the master protocol, the study investigators at
share responsibility 
with Boehringer Ingelheim International GmbH (BI) for the design of this multi-country
study. The investigators are responsible for conducting the multi-country study in a manner 
that meets regulatory standards, conducting analyses, and preparing scientific reports. The 
multi-country study shall be conducted as described in this approved master protocol. The 
authors will not develop or implement any deviation or change to the master protocol without 
prior review by BI.
The financial sponsor of this study is BI. The sponsor is responsible for ensuring the progress 
of the study. BI is also responsible for communicating with regulatory agencies about the 
master protocol, the progress of the study, and study results.

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of the finished medicinal 
product:
Jardiance®
Name of active ingredient:
Empagliflozin (A10BK03)
Protocol date:
Study number:
Version/Revision:
Version/Revision 
date:
29 November 2018
1245.195
2.0
11 October 2019
Title of study:
Multi-country non-interventional study on the effectiveness and safety of 
Empagliflozin in adult patients with type 2 diabetes in Europe and Asia
Rationale and 
background:
Type 2 diabetes mellitus (T2DM) is associated with high cardiovascular 
morbidity and mortality. Certain novel pharmacological treatments of 
T2DM, such as sodium-glucose cotransporter-2 (SGLT-2) inhibitors, have 
shown protective effects on cardiovascular (CV) events, CV mortality and 
all-cause mortality, in addition to glucose-lowering effects. The beneficial 
effects on CV events and mortality, as well as on renal events, have been 
observed in clinical trials and in observational studies. However, no 
observational study has focused specifically on CV events and mortality 
associated with empagliflozin use in Europe or Asia. Previous studies 
investigating safety outcomes have shown diverse results. Further studies 
are needed to confirm the association between use of empagliflozin or any 
SGLT-2 inhibitor and effectiveness and safety events in patient 
populations with T2DM representing real-world practice.
Research question 
and objectives:
The overall objective of this study is to examine effectiveness, safety, 
health care resource utilization (HCRU), and cost of care outcomes 
associated with the use of empagliflozin or any SGLT-2 inhibitors, 
compared with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors, among 
patients with T2DM. The primary objectives related to effectiveness are to 
examine the risk of hospitalization for heart failure, all-cause mortality and 
two composite outcomes: one including hospitalization for heart failure 
and all-cause mortality and another including myocardial infarction (MI), 
stroke, and all-cause mortality. The secondary objectives related to 
cardiovascular effectiveness are to examine the risk of cardiovascular 
mortality, coronary revascularization procedures, and two composite 
outcomes: 
one 
including 
hospitalization 
for 
heart 
failure 
and 
cardiovascular mortality and another including MI, stroke, and 
cardiovascular mortality (i.e. 3-point major adverse cardiovascular events 
[MACE]). Further secondary objectives related to renal effectiveness are to 

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001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of the finished medicinal 
product:
Jardiance®
Name of active ingredient:
Empagliflozin (A10BK03)
Protocol date:
Study number:
Version/Revision:
Version/Revision 
date:
29 November 2018
1245.195
2.0
11 October 2019
examine the risk of end-stage renal disease (ESRD), estimated glomerular 
filtration rate (eGFR) decline, progression to micro- or macroalbuminuria, 
and a composite outcome, including an eGFR decline and a progression to 
micro- or macroalbuminuria. The secondary objectives related to safety are 
to compare the risk of bone fractures, diabetic ketoacidosis, severe 
hypoglycemia, lower-limb amputation, and acute kidney injury requiring 
dialysis. Further secondary objectives are to examine HCRU and cost of 
care. 
The objectives related to effectiveness will be investigated by comparing 
patients initiating treatment with empagliflozin to patients initiating 
treatment with any DPP-4 inhibitor, as well as patients initiating treatment 
with any SGLT-2 inhibitor and patients initiating treatment with any DPP-
4 inhibitor. The secondary objectives on safety outcomes, HCRU, and cost 
of care will be investigated for empagliflozin and DPP-4 inhibitor exposure
only.
Study design:
This will be a non-interventional, multi-country cohort study using 
secondary data sources in European and Asian countries. This master 
protocol is an overarching protocol for the multi-country study. Individual-
level anonymous datasets will be analyzed in the included countries, using 
localized protocols adapted from this master protocol. The analyses of 
effectiveness outcomes will include exposure to empagliflozin and SGLT-
2 inhibitors, on the other hand, safety outcomes, HCRU, and cost of care 
will be investigated for empagliflozin only. The comparator drugs for all 
outcomes are DPP-4 inhibitors. To meet the objectives of this multi-
country study, aggregate-level results obtained from the countries will be 
combined: effectiveness and safety results will be pooled in a meta-
analysis, while HCRU and cost of care results will be presented
descriptively.
Population:
This study will include adults (≥18 years) with T2DM in Denmark, 
Finland, Germany, Israel, Japan, Norway, South Korea, Spain, Sweden, 
Taiwan, and the United Kingdom. The study population will consist of 
three sub-cohorts: patients initiating empagliflozin use, patients initiating 

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001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of the finished medicinal 
product:
Jardiance®
Name of active ingredient:
Empagliflozin (A10BK03)
Protocol date:
Study number:
Version/Revision:
Version/Revision 
date:
29 November 2018
1245.195
2.0
11 October 2019
any SGLT-2 inhibitor use, and patients initiating any DPP-4 inhibitor use. 
Variables:
The main exposures in this multi-country study are incident use of
empagliflozin (Anatomical Therapeutic Chemical [ATC]: A10BK03,
A10BD20) and incident use of any SGLT-2 inhibitor (A10BK). The 
comparator will be incident use of any DPP-4 inhibitor (A10BH). 
Incident use of empagliflozin and any SGLT-2 inhibitor will be defined as 
the first dispensation or any other record of the drug use after the drugs 
received marketing authorization, and not having any dispensation or any 
other record of the drug use of any SGLT-2 inhibitor or DPP-4 inhibitor 
during the preceding 12 months. Incident use of any DPP-4 inhibitor 
during the corresponding study period of empagliflozin or any SGLT-2 
inhibitor will be defined as first dispensation or any other record of the 
drug use after 12 months with no dispensation or any other record of any 
DPP-4 inhibitor or SGLT-2 inhibitor use. Exposure periods will be defined 
based on available data on dispensations or any other records of the drug
use in each data source. A grace period of 100% will be utilized to account 
for administration uncertainty. 
Variables related to the primary and secondary effectiveness outcomes will 
be cardiovascular events (MI, stroke, hospitalization for heart failure, 
coronary revascularization procedure), all-cause and cardiovascular 
mortality, diagnosis of ESRD, serum creatinine measurements, and 
albuminuria measurements.
Additionally, diagnoses associated with 
healthcare encounters, including hospitalizations and specialist outpatient 
and primary care encounters, and dispensation or any other record of the 
high-ceiling diuretics (loop diuretics) will be used for secondary definition 
of heart failure. Also, the composite outcomes will be based on these 
variables. Variables related to the safety outcomes will be diagnoses of 
bone fractures, diabetic ketoacidosis, severe hypoglycemia, lower-limb 
amputation, and acute kidney injury requiring dialysis. Other secondary 
outcomes related to HCRU will be the use of inpatient or outpatient 
services and drug use. The cost of care will be defined as the costs 
associated with the use of these resources. 

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001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of the finished medicinal 
product:
Jardiance®
Name of active ingredient:
Empagliflozin (A10BK03)
Protocol date:
Study number:
Version/Revision:
Version/Revision 
date:
29 November 2018
1245.195
2.0
11 October 2019
Other variables collected from the data sources, according to data 
availability, will include covariates at baseline on sociodemographic 
characteristics, related to lifestyle, diabetes complications, other 
comorbidities, laboratory values, prior/concomitant use of other 
antidiabetic drugs, prior use of other drugs, healthcare resource utilization 
covariates, and cost covariates. 
Data sources:
This study will utilize nationwide healthcare registers, regional quality 
registers, regional high-quality medical health records, and other health 
claims data available in Denmark, Finland, Germany, Israel, Japan, 
Norway, South Korea, Spain, Sweden, Taiwan, and United Kingdom. 
Study size:
With a baseline outcome rate of 1.5% per year (e.g. heart failure), the 
analyses are sufficiently powered (>80%) to detect 30% decrease in the 
baseline rate with 20,000 patients per sub-cohort, i.e., 40,000 patients in 
total, and 0.5 years of follow-up per patient. The anticipated number of 
patients varies per country and in total is expected to be over 150,000.
Data analysis:
In the analyses performed in each country, propensity score (PS) matching 
will be used to reduce confounding in the comparative analyses across 
study sub-cohorts. Pairwise PS models between i) empagliflozin sub-
cohort and DPP-4 sub-cohort and ii) SGLT-2 sub-cohort and DPP-4 sub-
cohort will be estimated using logistic regression including appropriate 
covariates. Standardized differences will be used to assess the success of 
matching, and variables with standardized difference 10% or greater will 
also be adjusted for in the outcome analyses.
For all included patients, descriptive statistics will be generated separately 
in each sub-cohort. Continuous covariates will be described by the mean, 
standard deviation, median, 25th, and 75th percentiles, minimum and 
maximum. Categorical covariates and continuous covariates that are also 
categorized will be described by proportion and frequency in each 
category.
The primary and secondary effectiveness outcomes, as well as the safety 
outcomes, will be analyzed and compared across sub-cohorts by incidence 
rates, cumulative-incidence plots, and Cox proportional hazards models.

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001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of the finished medicinal 
product:
Jardiance®
Name of active ingredient:
Empagliflozin (A10BK03)
Protocol date:
Study number:
Version/Revision:
Version/Revision 
date:
29 November 2018
1245.195
2.0
11 October 2019
However, the change of eGFR value in time will be described by moving 
averages and compared across sub-cohorts by linear regression models.
For the secondary outcomes on HCRU and cost of care, the number of
outpatient and inpatient healthcare visits, dispensations or other records of
drug use, and amount of costs will be determined during the follow-up (per 
years of follow-up, and per member per month). Comparison across sub-
cohorts will be done using generalized linear regression models.
 
 
In analyses combining the results from each country, meta-analyses will be 
performed for the primary and secondary effectiveness outcomes as well as 
safety outcomes to combine individual country-level results. Subgroups of 
countries (e.g. Nordic, European or Asian countries) will also be included 
in separate meta-analyses. Country-level results on HCRU and cost of care
will be presented descriptively.
Milestones:
In this multi-country study, the start of data collection is in Q1 2019, and 
the end of data collection in Q1 2021. The first interim data report with 
combined results from the selected countries is planned to be available in 
Q4 2019. At least one additional interim data report and analyses will be 
conducted as needed before completing the final report with all study 
results from the countries in Q1 2021.

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5.
AMENDMENTS AND UPDATES
Amendment 
Number
Date
Section of 
the study 
protocol
Amendment or 
update
Reason
1
13 September
2019
Multiple
New renal and 
safety outcomes 
included
To demonstrate an 
association of the 
study drug and the 
relevant safety
outcomes.
Multiple
Update of the index 
date
To align with the 
US study protocol. 
Multiple
Update of the 
inclusion/exclusion 
criteria
To improve the 
precision and 
comprehensiveness 
of the study group 
selection.
Multiple
Safety outcomes 
and, healthcare 
resource utilization 
and cost analyses 
will be performed 
exclusively for 
empagliflozin as the 
exposure group and 
DPP-4 inhibitors as 
the comparison 
group
To have drug-
specific safety 
outcomes and 
healthcare 
utilization and costs
Multiple
Other minor 
amendments
To implement 
updates holistically.

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6.
MILESTONES
The following table estimates timelines for the milestones of this multi-country study,
combining results from each country; country-level timelines for the country-specific studies
will be detailed in localized protocols.
Milestone
Planned Date
Start of data collection1
Q1 2019
End of data collection2
Q1 2021
Interim data reports3
Q4 2019 and Q1 2021
Registration in the EU PAS register
Q4 2018
Final report of study results4
Q1 2021
1 In any country; 2 In the last country; 3 At least two interim reports will be performed, including combined results of the 
countries for which results were available between Q3 2019 and Q4 2020; 4 Including combined results from all 
countries. 
7.
RATIONALE AND BACKGROUND
The number of patients with type 2 diabetes mellitus (T2DM) is increasing all over the world 
[R15-1988]. In Europe, the number of patients with diabetes is estimated to be 55 million, 
and it is estimated to increase to 67 million by 2030. The corresponding increase in the
Western Pacific is from 77 million to 113 million. T2DM constitutes 90% of these numbers.
Cardiovascular (CV) diseases are considerable comorbidities among patients with T2DM 
[R18-3510]. Up to one-third of patients with T2DM experience adverse CV events, such as 
atherosclerosis, coronary heart disease, heart failure, angina, myocardial infarction (MI), and 
stroke. Further, CV events are the cause of death for 20% of patients with T2DM [R18-3508]. 
The high CV morbidity also contributes to increasing healthcare costs [R18-3509]. A 
systematic review found that in comparison to T2DM patients who do not have CV diseases, 
CV events contribute to a 112% increase in healthcare costs, with stroke being the event with 
the highest increase in costs among patients with T2DM [R18-3509]. CV events contribute to 
up to 50% of healthcare costs in the treatment of T2DM. The main cost drivers are 
hospitalization, drug, and outpatient care costs.
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors represent one of the most recent 
pharmacological treatment options of T2DM [P17-01701]. These drugs have been available 
since 2012. The globally available SGLT-2 inhibitors include canagliflozin, dapagliflozin, 
empagliflozin, and ertugliflozin. Additional SGLT-2 inhibitors (e.g. ipragliflozin, 
tofogliflozin) are available also in Asia [P17-01701]. Generally, SGLT-2 inhibitors are not
the first-line treatment, instead, they are often used mainly later in the disease course of 

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T2DM [P18-10828]. In addition to the glucose-lowering effects, these drugs also have 
beneficial effects on weight, blood pressure, and potentially also lipids [P17-01701]. 
In large CV outcome trials, empagliflozin and canagliflozin use decreased the risk of adverse 
CV events among patients with T2DM compared to the placebo group [P18-04466]. Both 
drugs showed to reduce the risk of CV mortality, non-fatal MI, and non-fatal stroke (a 
composite outcome referred to as 3-point major adverse cardiovascular events [MACE]) by 
14%. Further, empagliflozin use reduced the risk of MI by 13%, while the risk of CV or all-
cause mortality and hospitalization for heart failure was reduced by 32-38%. Also, renal 
outcomes have been investigated: dapagliflozin and canagliflozin decreased the risk of eGFR 
decline, and canagliflozin also decreased the risk of progression of albuminuria [P18-02804, 
P19-04731]. However, the patients included in these trials had high CV morbidity and thus 
the results might not be generalizable to with a broader population of patients with T2DM
including those with fewer CV risk factors. 
Observational studies have found an association between the use of dapagliflozin or any 
SGLT-2 inhibitor and a decreased risk of CV events and mortality compared to other 
glucose-lowering drugs among broader populations of T2DM patients [R18-3505, P17-
05895, P18-06283, P17-08964]. Dapagliflozin/any SGLT-2 inhibitor use has been associated 
with a 40-50% decrease in the risk of all-cause mortality [R18-3505] and a 30-40% decrease 
in the risk of heart failure [R18-3505, P17-05895, P18-06283, P17-08964]. Dapagliflozin/any 
SGLT-2 inhibitor use has also been associated with a lower risk of 3-point MACE. The 
previous results on the risk of MI, stroke, and CV mortality associated with dapagliflozin/any 
SGLT-2 inhibitor use have been directionally consistent, suggesting decreased risks, but the
results of the studies have been inconsistent in detecting significant associations [R18-3505, 
P18-06283, P17-08964]. The proportion of empagliflozin use in the studies investigating any 
SGLT-2 inhibitor has been <10% [P17-05895, P18-06283, P17-08964 ] and, therefore, the 
results may not be generalizable to empagliflozin users. Preliminary results from a study 
being performed in the United States of America found that empagliflozin was associated 
with a 49% decrease in heart failure risk. To our best knowledge, no study has investigated 
the CV benefits associated with empagliflozin use in a real-world setting in Europe or in 
Asia.
Previous studies, including clinical trials and observational studies, have shown diverse
results regarding empagliflozin, dapagliflozin, canagliflozin or any SGLT-2 inhibitor use and 
the risk of safety events among patients with T2DM. Risk of diabetic ketoacidosis is similar 
between empagliflozin or canagliflozin users and placebo group [P18-02804, P18-01920].
However, diabetic ketoacidosis was more frequent among dapagliflozin users in comparison 
to the placebo group (hazard ratio [HR] 2.18; 95% CI 1.10 to 4.30) [P19-04731]. Moreover, 
in a register-based cohort study, the associated risk of diabetic ketoacidosis was increased 
(HR, 2.14; CI, 1.01 to 4.52) among patients with T2DM using SGLT2 inhibitors, compared 
with glucagon-like peptide 1 receptor agonist users [P18-10986]. Further, dapagliflozin use 

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has also been found to decrease the risk of acute kidney injuries in a clinical trial (HR, 0.69; 
95% CI, 0.55 to 0.87) [P19-04731] while no difference was observed between users of 
canagliflozin and placebo [P18-02804]. Further, no association was found in an observational 
study that compared SGLT-2 inhibitor use with glucagon-like peptide 1 receptor agonist drug 
use (HR, 0.69; CI 0.45 to 1.05) [P18-10986].
The frequency of fractures was similar between users of empagliflozin and placebo (3.9% vs. 
3.8%, respectively) [P18-01920] and dapagliflozin and placebo (5.3% vs. 5.1%, respectively)
[P19-04731]. On the contrary, the frequency of fractures was higher among canagliflozin 
users in comparison to placebo (HR 1.26; 95% CI 1.04 to 1.52) [P18-02804]. SGLT-2 
inhibitor use was not associated with an increased risk of bone fracture at a register-based 
cohort study, compared with glucagon-like peptide 1 receptor agonist users (HR, 1.11; CI
0.93 to 1.33) [P18-10986].
There was no difference in the frequency of amputations between dapagliflozin and placebo 
group (1.4% vs. 1.3%) [P19-04731]. However, canagliflozin use has shown a greater risk of 
amputations (HR, 1.97; 95% CI, 1.41 to 2.75) compared with placebo [P18-02804]. In 
addition, a register-based cohort study found an association with an increased risk of lower 
limb amputation (HR, 2.32; CI, 1.37 to 3.91) among patients with T2DM using SGLT2 
inhibitors, compared with glucagon-like peptide 1 receptor agonist users [P18-10986].
Further real-world evidence studies are needed to examine the association between 
empagliflozin use and adverse CV events as well as mortality. It is especially important to 
account for confounding by indication in observational studies. The previous observational 
studies investigating the association between SGLT-2 inhibitors and adverse CV events and 
mortality compared new users of SGLT-2 inhibitors with new users of other glucose-
lowering drugs. This may have resulted in residual confounding and, thus, biased results, 
since SGLT-2 inhibitors are not the first-line treatment of T2DM. Immortal time bias, 
resulting from a comparison of first-line treatment and drugs used mainly later in the disease 
course, may have contributed to the major differences between SGLT-2 inhibitors and other 
glucose-lowering drugs. Further, comparison with other glucose-lowering drugs means that 
patients with the first-line treatment of T2DM, but also patients with a more severe stage of 
the disease, might have been included in the comparison group. Alternatively, SGLT-2 
inhibitor use can be compared with drugs that are used in the treatment of a similar line in the 
treatment pathway of T2DM [P18-10828]. For example, dapagliflozin use has been compared 
with dipeptidyl peptidase-4 (DPP-4) inhibitor use [R18-3505], and the study found that 
dapagliflozin use was associated with a decreased risk of hospitalization for heart failure, all-
cause mortality, and 3-point MACE, but not of MI, stroke, and CV mortality. Further, the 
specific inclusion and exclusion criteria in the clinical trials [P18-02804, P19-04731, P18-
01920] limit the generalizability of the results and more studies are needed to examine the 
association between empagliflozin/any SGLT-2 inhibitor use and renal events as well as 
safety outcomes.

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This study will be an expansion of the non-interventional study being conducted in the United 
States of America (EMPRISE, 1245.92) with additional renal effectiveness outcomes. New 
users of empagliflozin and new users of any SGLT-2 inhibitor will be compared with new 
users of DPP-4 inhibitors in several European and Asian countries. The effectiveness
outcomes of interest include non-fatal and fatal CV events, all-cause and CV mortality.
Further effectiveness outcomes are coronary revascularization procedures, end-stage renal 
disease (ESRD), estimated glomerular filtration rate (eGFR) decline, a progression from 
normoalbuminuria to micro- or macroalbuminuria, and derived cardiovascular and renal 
composite outcomes. In addition, safety outcomes, i.e. risk of bone fractures, diabetic 
ketoacidosis, severe hypoglycemia, lower-limb amputation, and acute kidney injury requiring 
dialysis, will be examined in this study. Furthermore, healthcare resource utilization (HCRU) 
and cost of care outcomes will be investigated.
8.
RESEARCH QUESTION AND OBJECTIVES
The overall objective of this study is to examine the effectiveness, safety, HCRU, and cost of 
care outcomes in patients with T2DM initiating empagliflozin or any SGLT-2 inhibitor use in 
comparison to patients with T2DM initiating any DPP-4 inhibitor use after propensity score
(PS) matching.
The specific objectives of this study are related to effectiveness (primary objectives 1-4, 
secondary objectives 1-8), safety (secondary objectives 9-13), HCRU (secondary objective 
14), and cost of care (secondary objective 15). The comparisons for objectives in sections 
8.1-8.3 will be performed between patients initiating empagliflozin or any SGLT-2 inhibitor 
use and patients initiating any DPP-4 inhibitor use. The comparisons in sections 8.4-8.5 will 
be performed between patients initiating empagliflozin use and patients initiating any DPP-4 
inhibitor use only.
8.1
PRIMARY OBJECTIVES: EFFECTIVENESS
Primary objective 1: Compare the risk of hospitalization for heart failure.
Primary objective 2: Compare the risk of all-cause mortality.
Primary objective 3: Compare the risk of a composite outcome including hospitalization for 
heart failure and all-cause mortality.
Primary objective 4: Compare the risk of a composite outcome including myocardial 
infarction (MI), stroke, and all-cause mortality, as well as its individual components.

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8.2
SECONDARY OBJECTIVES ON CARDIOVASCULAR 
EFFECTIVENESS
Secondary objective 1: Compare cardiovascular (CV) mortality.
Secondary objective 2: Compare the risk of a composite outcome including hospitalization 
for heart failure and cardiovascular (CV) mortality.
Secondary objective 3: Compare the risk of 3-point major adverse cardiovascular (CV) 
events (MACE), defined as a composite outcome including myocardial infarction (MI), 
stroke, and cardiovascular (CV) mortality
Secondary objective 4: Compare the risk of coronary revascularization procedure.
8.3
SECONDARY OBJECTIVES ON RENAL EFFECTIVENESS
Secondary objective 5: Compare the risk of end-stage renal disease (ESRD).
Secondary objective 6: Compare the risk of estimated glomerular filtration rate (eGFR)
decline.
Secondary objective 7: Compare the risk of progression from normoalbuminuria to micro-
or macroalbuminuria.
Secondary objective 8: Compare the risk of composite outcome including eGFR decline and 
progression from normoalbuminuria to micro- or macroalbuminuria.
8.4
SECONDARY OBJECTIVES ON SAFETY
Secondary objective 9: Compare the risk of bone fractures.
Secondary objective 10: Compare the risk of diabetic ketoacidosis.
Secondary objective 11: Compare the risk of severe hypoglycemia.
Secondary objective 12: Compare the risk of lower-limb amputation.
Secondary objective 13: Compare the risk of acute kidney injury requiring dialysis.

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8.5
SECONDARY OBJECTIVES ON HEALTH CARE RESOURCE
UTILIZATION (HCRU) AND COST OF CARE
Secondary objective 14: Compare healthcare resource utilization (HCRU) during the follow-
up period.
Secondary objective 15: Compare the cost of care outcomes during the follow-up period.

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This will be a non-interventional, multi-country cohort study using existing data and 
including adults (≥18 years) with a diagnosis of T2DM. All data will be obtained from 
electronically recorded longitudinal secondary data sources, separately in each included 
country. In each country, patients initiating treatment with empagliflozin or any other SGLT-
2 inhibitor will be compared with PS-matched patients initiating treatment with any DPP-4 
inhibitor (Figure 1; specific comparisons presented in section 8).
Figure 1
Overview of the study periods and comparison pairs in the analyses: 
a) Analyses comparing empagliflozin use with DPP-4 inhibitor use; 
b) Analyses comparing SGLT-2 inhibitor use with DPP-4 inhibitor 
use.
AT=as treated; DPP-4=dipeptidyl peptidase-4; MA=marketing authorization; PS=propensity score; 
SGLT-2=sodium-glucose cotransporter-2.
1 In analyses investigating effectiveness or safety outcomes, the occurrence of the outcome in question will be observed until 
the end of the follow-up (e.g. while investigating hospitalization for heart failure, the follow-up will not end at the 
occurrence of a stroke).
2 In analyses investigating safety outcomes, an exposure risk window will be accounted for after discontinuation.
By comparing new users of empagliflozin or new users of any SGLT-2 inhibitor with an 
active comparator, i.e. new users of any DPP-4 inhibitor, confounding by indication can be 
decreased as the compared sub-cohorts have similar indications [R18-3506]. Further, the 

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inclusion of eligible patients from multiple countries increases the power of the analyses and 
generalizability of the results.
9.1.1
Country-specific studies as components of this multi-country study
This master protocol is an overarching protocol for the multi-country study (Figure 2). 
Country-specific adaptations of this master protocol will be described in localized protocols
(Figure 2), written separately in each included country. As illustrated in Figure 2, individual-
level data will be analyzed as part of the country-specific studies. To meet the objectives of 
this multi-country study, aggregate-level results obtained from the countries will be combined
in the multi-country study: effectiveness and safety results will be pooled in a meta-analysis,
while HCRU and cost results will be presented descriptively.
Figure 2
Overview of the country-specific studies as components of the multi-
country study.
HCRU=health care resource utilization; SAP=statistical analysis plan.

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9.2
SETTING
9.2.1
Overview
The study will be performed at least in 11 countries: Denmark, Finland, Germany, Israel, 
Japan, Norway, South Korea, Spain, Sweden, Taiwan, and the United Kingdom. Additional 
countries may be included during the course of this study. The dates of marketing 
authorizations (MA) of empagliflozin, the first available SGLT-2 inhibitor, and the first 
available DPP-4 inhibitor in the participating countries are presented in Table 1. If additional 
countries are included in the study, the corresponding MA dates will be specified in the 
localized protocol.
Table 1
Marketing authorizations of empagliflozin, first available SGLT-2 
inhibitor, and first available DPP-4 inhibitor in each study country.
Country
Date of 
empagliflozin MA
Date of first SGLT-
2 inhibitor MA
Date of first DPP-4 
inhibitor MA
Denmark
May 2014
November 2012
March 2007
Finland
May 2014
November 2012
March 2007
Germany
May 2014
November 2012
March 2007
Israel
August 2015
August 2014
June 2008
Japan 
December 2014
January 2014
October 2009
Norway
May 2014
November 2012
March 2007
South Korea
August 2014
November 2013
September 2007
Spain
May 2014
November 2012
March 2007
Sweden 
May 2014
November 2012
March 2007
Taiwan
May 2016
May 2016
March 2009
The United Kingdom
August 2014
November 2012
April 2007
DPP-4=dipeptidyl peptidase-4; MA=marketing authorization; SGLT-2=sodium-glucose cotransporter-2.

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New users of empagliflozin will be identified between the MA date of empagliflozin (May 
2014 onwards) and the end of data availability (not later than December 2018) in each 
country (Table 1, Figure 1). A similar approach will be utilized in defining new users of any 
SGLT-2 inhibitors, and new users will be identified between the MA date of first available 
SGLT-2 inhibitor (November 2012 onwards) and end of data availability. New users of any 
DPP-4 inhibitor will be identified during the corresponding study periods of empagliflozin 
and any SGLT-2 inhibitor (Table 2, Figure 1).
Table 2
Definitions of investigated sub-cohorts of patients with type 2 
diabetes mellitus included in this study.
Sub-cohort
Definition
The index date
Empagliflozin 
sub-cohort
Patients who initiate1 empagliflozin
use during the study period and 
meet criteria in Figure 1 and Figure 
4 in section 9.2.2.
The first dispensation date or the 
first date of any other record of the 
empagliflozin use after the MA 
date2 of empagliflozin
Any SGLT-2 
inhibitor sub-
cohort
Patients who initiate1 any SGLT-2 
inhibitor use during the study period
and meet criteria in Figure 1 and 
Figure 4 in section 9.2.2.
The first dispensation date or the 
first date of any other record of 
any SGLT-2 inhibitor use after the 
MA date3 of first SGLT-2 
inhibitor
Any DPP-4 
inhibitor sub-
cohort
Patients who initiate1 any DPP-4 
inhibitor use during the study period
and meet criteria in Figure 1 and 
Figure 4 in section 9.2.2.
The first dispensation date or the 
first date of any other record of 
any DPP-4 inhibitor use during the 
study period4.
1 New use will be defined as having no dispensations or any other record of drug use for any SGLT-2 inhibitor or any DPP-4 
inhibitor during the previous 12 months; 2 Range from May 2014 to May 2016; 3 Range from November 2012 to May 
2016; 4 The study period starts at empagliflozin MA date in analyses with empagliflozin and at first SGLT-2 inhibitor 
MA date in analyses with any SGLT-2 inhibitors. 
T2DM=type 2 diabetes mellitus; DPP-4=dipeptidyl peptidase-4; MA=marketing authorization; SGLT-2=sodium 
glucose cotransporter 2.
New use of empagliflozin, any SGLT-2 inhibitor, and any DPP-4 inhibitor will be defined as 
not having any dispensation or any other record of the drug use of these drugs during the 
preceding 12 months. The index date will be defined as the date of the first dispensation or 
any other record of the use of the sub-cohort-defining drug, forming three sub-cohorts: 
empagliflozin sub-cohort, any SGLT-2 inhibitor sub-cohort, and any DPP-4 inhibitor sub-
cohort (Table 2). Data on comorbidities, other drug use, and clinical variables will be 
obtained from the pre-index period, i.e. 12 months before (and including the date of) the 
index date (Figure 3).

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Figure 3
Definitions of the pre-index period and follow-up in relation to the 
index date.
9.2.2
Study population
To study real-world treatment patterns, the study population will include a broad spectrum of 
users of empagliflozin, any SGLT-2 inhibitor, and any DPP-4 inhibitor. The following 
inclusion and exclusion criteria will be used (definitions detailed in ANNEX 5):
Inclusion criteria (Figure 4):
Dispensation or any other record of empagliflozin, any SGLT-2 inhibitor, or any DPP-4 
inhibitor use during the study period (Figure 1)
No dispensation or any other record of any other SGLT-2 inhibitor or DPP-4 inhibitor1 use 
during the 12 months preceding the index date, and 
Having a diagnosis of T2DM before the index date, based on ICD-10 codes or other available 
data2.
Exclusion criteria (Figure 4):
Aged <18 years on the first dispensation date or date of the first record of empagliflozin, any 
SGLT-2 inhibitor or any DPP-4 inhibitor use,
Pre-existing diagnosis of T1DM during the 12 months before the index date2,
Pre-existing diagnosis of secondary diabetes or gestational diabetes in the 12 months 
prior to the index date2,
Having a diagnosis of ESRD during the 12 months before the index date,
<12 months of available data before the index date, and/or no complete history of
drug dispensations/other records of drug use during this period, and 
Missing or ambiguous data on age or sex.
                                                
1 Including possible SGLT-2 inhibitors or DPP-4 inhibitors that are marketed locally and are not study drugs of this multi-
country study (Table 3). Patients are also excluded if they are at the index date dispensed both a SGLT-2 inhibitor and 
a DPP-4 inhibitor, or if records of use are available for both, in free or fixed-dose combination.
2 The definition of T2DM, T1DM, and other types of diabetes, including the used diagnosis, drug or other data and the most 
appropriate time-window prior to the index date, will be detailed in the localized protocols according to validated or 
standard definitions used in the country and data source.

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Figure 4
Flow chart
DPP-4=dipeptidyl peptidase-4; SGLT-2=sodium-glucose cotransporter-2; T1DM=type 1 diabetes mellitus; T2DM=type 2 
diabetes mellitus.
These criteria ensure that only patients with T2DM, and not any other type of diabetes, are 
included in the study. In addition, the exclusion of patients with unknown drug use data due 
to, for example, nursing home stay, ensures that the included patients have sufficient 
exposure data available.

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9.2.3
Study period and follow-up
The duration of the study period depends on the dates of the marketing authorizations of the 
study drugs (Table 1) and data availability in each country’s data sources and shall be 
detailed in each localized protocol. For all PS-matched patients, the follow-up will begin on 
the index date and potentially continue for all as long as data are available in the used data 
sources, up to December 2018. However, if the follow-up ends (see below) at the same 
(index) date, the patient will not contribute to the outcome analyses, i.e., that patient will
account for 0 person-years and 0 events, even if follow-up ended due to an outcome 
happening at the index date (e.g. death). The minimum follow-up time will be 1 day for each 
patient who contributes to the outcome analyses, and the follow-up time contributing to the 
analyses starts one day after the index date. Specifically, follow-up time will be 1 day for any 
patient whose follow-up ends at the day following the index date. The duration of follow-up 
will be computed as follows: (date of ending the follow-up – index date). The rationale for 
this decision to handle these expectedly rare events is that in several countries the timing of 
event occurrence can only be determined with a 1-day precision. Each patient will be 
included only once in each sub-cohort.
In the main analyses, the follow-up will end on the date of the first occurrence of any of the 
following events: occurrence of an effectiveness or a safety outcome (when studying 
outcomes related to effectiveness or safety), death, discontinuation of the initial drug, switch 
to any other study drug (empagliflozin, any SGLT-2 inhibitor, any DPP-4 inhibitor)3,
initiation of concomitant use of empagliflozin/SGLT-2 inhibitor and a DPP-4 inhibitor (either 
as free or fixed-dose combinations)4 or two drugs within the same class (i.e. two SGLT-2 
inhibitors or two DPP-4 inhibitors), or end of data availability (Figure 1). Depending on the 
data source, the end of data availability could result from, for example, moving to another 
region or admission to institutional care. When studying the HCRU and cost of care 
outcomes, the follow-up is not censored at the occurrence of an effectiveness or a safety 
outcome.
9.3
VARIABLES
The variable definitions presented in this master protocol are master definitions, which shall 
be adapted in each country and detailed in the localized protocols (ANNEX 3). The master 
definitions concerning diagnoses and procedures are in this master protocol provided using 
the International Classification of Diseases, both 9th (ICD-9) and 10th revision (ICD-10) 
codes. The master definitions concerning drugs are in this master protocol provided using the 
Anatomical Therapeutic Chemical (ATC) codes. Both ICD and ATC codes shall be adapted 
                                                
3 The follow-up time will be censored also at switch to SGLT-2 inhibitors or DPP-4 inhibitors that are marketed locally and 
are not study drugs in this multi-country study (Table 3).
4 The follow-up time will be censored also at initiation of concomitant use of SGLT-2 inhibitors or DPP-4 inhibitors that are 
marketed locally and are not study drugs in this multi-country study (Table 3).

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to locally used coding systems (or other definitions) and detailed in the localized protocols. 
The diagnoses in the localized protocols should be identified from recorded diagnoses, claims 
or other applicable secondary data. Furthermore, the used data sources shall be detailed in 
section 9.4, providing information on the type of data and healthcare setting where the data 
have been retrieved, including whether the drug use data are based on dispensations or other 
records (e.g. prescriptions) and whether primary care is included.
9.3.1
Exposures: study drugs
Main exposures: empagliflozin and any SGLT-2 inhibitor
The main exposures in this study are incident use of empagliflozin (ATC codes: A10BK03, 
A10BD20) and incident use of any SGLT-2 inhibitor. The globally available SGLT-2 
inhibitors to be included in any SGLT-2 inhibitor sub-cohort are canagliflozin, dapagliflozin, 
empagliflozin, ertugliflozin, and ipragliflozin (Table 3). Fixed-dose combination drugs with a 
SGLT-2 inhibitor and another drug other than a DPP-4 inhibitor (comparator) will be 
included. Other available SGLT-2 inhibitors available in specific countries may be included
as study drugs in the country-specific studies (ANNEX 3). The results of such country-
specific analyses will not be included in the combined results of the multi-country study.
For the secondary objectives on safety, HCRU and costs (see sections 8.4 and 8.5), the main 
exposure of interest is exclusively empagliflozin, and thus any SGLT-2 inhibitor users will 
not be analyzed.
Comparator drugs: any DPP-4 inhibitor
Incident use of any DPP-4 inhibitor is the main comparator in the analyses. The globally 
available DPP-4 inhibitors to be included in any DPP-4 inhibitor sub-cohort are presented 
inTable 3. Fixed-dose combination drugs with a DPP-4 inhibitor and another drug other than 
a SGLT-2 inhibitor (main exposure) will be included. The DPP-4 inhibitors will be used as 
the active comparator sub-cohort because they are used in the treatment of the same disease 
stage of T2DM as SGLT-2 inhibitors [P15-09840]. Further, most DPP-4 inhibitors have not 
been associated with a risk of CV outcomes [P18-04466].
 
 
In localized protocols, alternative comparator drugs may be included. For example, DPP-4 
inhibitors are used as a first-line treatment of T2DM in Japan and, consequently, alternative 
comparator drugs reflecting local treatment practices will have to be included in the country-
specific analyses. The results of such country-specific analyses with alternative comparator 
drugs will not be included in the combined results of the multi-country study (ANNEX 3).

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Table 3
Study drugs forming the sub-cohorts.
Sub-cohorts and study drugs 
ATC code
Empagliflozin (including fixed-dose combinations with any other drug than DPP-4 
inhibitor1)
Empagliflozin
A10BK03 (A10BX122)
Empagliflozin and metformin
A10BD20
Any SGLT-2 inhibitor (including fixed-dose combinations with a SGLT-2 inhibitor 
and any other drug than DPP-4 inhibitor1)
Dapagliflozin
A10BK01 (A10BX092)
Dapagliflozin and metformin
A10BD15
Empagliflozin
A10BK03 (A10BX122)
Empagliflozin and metformin
A10BD20
Canagliflozin
A10BK02 (A10BX112)
Canagliflozin and metformin
A10BD16
Ertugliflozin
A10BK04
Ertugliflozin and metformin
A10BD23
Ipragliflozin
A10BK05
Any DPP-4 inhibitor (including fixed-dose combinations with a DPP-4 inhibitor and 
any other drug than SGLT-2 inhibitor1)
Sitagliptin
A10BH01
Sitagliptin and metformin
A10BD07
Sitagliptin and pioglitazone
A10BD12
Sitagliptin and simvastatin
A10BH51
Vildagliptin
A10BH02
Vildagliptin and metformin
A10BD08
Saxagliptin
A10BH03
Saxagliptin and metformin
A10BD10
Alogliptin
A10BH04
Alogliptin and pioglitazone
A10BD09

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Table 3 (cont'd)
Study drugs forming the sub-cohorts.
Sub-cohorts and study drugs 
ATC code
Any DPP-4 inhibitor (including fixed-dose combinations with a DPP-4 inhibitor and 
any other drug than SGLT-2 inhibitor1)
Alogliptin and metformin
A10BD13
Linagliptin
A10BH05
Linagliptin and metformin
A10BD11
Gemigliptin
A10BH06
Gemigliptin and rosuvastatin
A10BH52
Gemigliptin and metformin
A10BD18
Evogliptin
A10BH07
Evogliptin and metformin
A10BD22
ATC=Anatomical Therapeutic Chemical; DPP-4=dipeptidyl peptidase-4; SGLT-2=sodium-glucose cotransporter-2
1 Includes combinations with other classes of antidiabetic drugs.
2 A previous version of the ATC code
Concomitant use of a SGLT-2 inhibitor and a DPP-4 inhibitor excluded
Concomitant use of a SGLT-2 inhibitor and a DPP-4 inhibitor will not be accounted for in 
this master protocol or in the combined analyses of the multi-country study. As described in 
section 9.2.2, the inclusion and exclusion criteria require that patients have no previous use of
any SGLT-2 inhibitor or any DPP-4 inhibitor (also those marketed locally but not listed as 
study drugs in Table 3), in free or fixed-dose combination.
During the follow-up, patients are censored if they switch to any SGLT-2 inhibitor or DPP-4 
inhibitor, or initiate a concomitant use of study drugs (free or fixed-dose combinations), as 
described in section 9.2.3 and in Figure 1.
However, concomitant use of a SGLT-2 inhibitor and a DPP-4 inhibitor may be detailed in 
the localized protocols to be included in the country-specific analyses; these results will not 
be included in the combined results of the multi-country study (ANNEX 3).
Definition of exposure periods
Exposure periods will be defined based on available data on drug dispensations or other 
records of the drug use in each country. If data on drug dispensations or prescriptions is not 
available in the data source, alternative definitions for exposure periods will be used,
provided in ANNEX 4.

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Drug use will be assumed to begin on the date of a dispensation or the date of any other 
record of the drug use. A supply will indicate the duration of exposure after a dispensation or 
any other record of the drug use (Figure 5). Supply will be defined for each dispensation or 
any other record of drug use based on available data on the daily dose, as detailed in the 
localized protocols. For example, the duration of the supply can be derived from the 
dispensed amount (total milligrams dispensed) and the daily dose (milligrams). If a daily dose 
is not readily available, the daily dose shall be estimated as appropriate in the local setting. If 
a subsequent supply occurs before the previous supply has finished, the start of the 
subsequent supply will be shifted. For example, if a patient receives the first supply for 60 
days and refills at day 50 for another 60 days, the duration of the two supplies combined will 
be 50+10+60=120 days, after shifting the start of the second supply with 10 days for which 
the patient had supply in storage from the first supply. To avoid artificially long exposure 
periods, however, a subsequent supply can be shifted with a maximum of 14 days, which is 
considered a reasonable time for patients to refill prior to the end of their ongoing supply. 
Further, a subsequent supply cannot be shifted over the grace period (as defined below).
Figure 5
Illustration of combining exposure periods with grace periods and the 
differences between the AT and ITT approaches.
AT=as-treated; GP=grace period; ITT=intention to treat
A grace period of 100% of the duration of the most recent supply will be included in the 
exposure period to account for uncertainty related to actual drug use patterns. The grace 
period will be defined from the most recent supply. In the above example on two overlapping 
supplies with 60 days, totaling in 120 days, the grace period is 60 days (100% of the most 
recent supply). Overlapping supplies and grace periods will be combined as exposure periods 
(Figure 5).
The discontinuation will be defined as the date of ending the grace period (Figure 6). The 
switch of a drug is defined as replacing one study drug by another, and no grace period will 
be used (Figure 6). The concomitant use addresses to the simultaneous use of study drugs, 
and the first date of concomitant use will end the follow-up, i.e., no grace period will be used
(Figure 6).

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Figure 6
Illustration of a study drug a) discontinuation; b) switch and c) 
concomitant use
An ‘as-treated ‘(AT) approach will be utilized in the main analyses. This means that the 
follow-up is censored at discontinuation, switch to other study drug, or concomitant use, as 
detailed in Figure 1. The outcomes related to effectiveness, safety, HCRU, and the cost of 
care will be observed until the end of the first continuous exposure to a study drug (Figure 5).

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When investigating the safety outcomes, a modified AT approach will be utilized in the main 
analyses with an additional exposure risk window of 30 days after discontinuation of drug use
(Figure 7), to consider potential lag in the occurrence of safety outcomes. The exposure risk 
window will be accounted for only in case of discontinuation of the drug use, and not when 
the follow-up ends at the switch of drug and starting concomitant use (Figure 1). 
Consequently, the risk period in these analyses will consist of the supply, grace period, and 
exposure risk window. The exposure risk window will not be used after switch or starting 
concomitant use because the safety associated with the initial drug is the main interest in 
these analyses.

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Figure 7
Illustration of the utilization of 30-day exposure risk window in the 
analyses with safety outcomes. Exposure risk window will be 
accounted for if the follow-up ends at discontinuation of drug use (a) 
but not at discontinuation for any other reason (b).
9.3.2
Outcomes
The outcome definitions shall be detailed in the localized protocols, using the master 
definitions presented in this master protocol (Table 4; more detailed definitions in
ANNEX 6).
Primary and secondary effectiveness outcomes
The primary and secondary effectiveness outcomes (Table 4) will be observed during the 
study period, and the occurrence of the outcome in question, excluding secondary outcome 
6b, will be observed until the end of the follow-up.
Secondary renal effectiveness outcomes
The baseline value for the secondary renal effectiveness outcomes 6-8 (Table 4) will be 
considered as the creatinine and/or albuminuria value that is closest to the index date during 
the pre-index period (Figure 3). The date of outcome for outcomes 6a, 7, and 8 is the date 
when the decline to abnormal status is observed. However, the first 4 weeks after the index 

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date will be disregarded in all analysis for the secondary outcomes 6-8, as empagliflozin 
seems to have some initial effects on eGFR decline [P18-09763].
If countries can define inpatient and outpatient visits, they could be preferable to use
outpatient measurements.
Definitions of different levels of eGFR and albuminuria are presented in ANNEX 6. The 
eGFR decline will be measured by utilizing serum creatinine and the change from normal
kidney function (≥60ml/min/1,73m2) to abnormal kidney function (<60ml/min/1,73m2) will 
be analyzed. The eGFR will be based on serum creatinine (SCr) measurements and the 2009 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation [R13-
4387]: 141*min(SCr/κ, 1)α *max(SCr/κ, 1)-1.209*0.993Age [*1.018 if female] [*1.159 if black], 
where κ is 0.7 for female and 0.9 for male whereas α is -0.329 for female and -0.411 for 
male. If ‘black’ is missing, the factor of 1 will be used. The min is the minimum of SCr/κ or 
1, and max is the maximum of SCr/κ or 1. In addition, the progression from 
normoalbuminuria (<30mg/g) to micro- or macroalbuminuria (≥30mg/g) will be based on the 
urine albumin-to-creatinine ratio.
Secondary safety outcomes
The safety outcomes (Table 4) will be observed during the study period, but if the follow-up 
ends at discontinuation, an exposure risk window will be accounted for (Figure 7). The 
occurrence of the outcome in question will be observed until the end of the follow-up. These 
analyses will focus on empagliflozin because the safety profile of the SGLT-2 inhibitors as a 
group might not be comparable [P18-02804, P19-04731, P18-01920].
Secondary outcomes on health care resource utilization and cost of care
Availability of cost data may vary across countries. If costs are recorded in the registers 
directly, they will be used as such. If not, costs of outpatient visits, inpatient stays, and the 
drug use will be evaluated indirectly by country-specific standards and associated with the 
observed number of different encounter types (Table 4). For example, the diagnosis-related 
group information about the cost of the outpatient visit, inpatient stay of 24-hours of a 
specific type, or general information about country-specific drug costs can be used and 
assigned to the observed number of resource use of this type. Quantities of HCRU for 
patients on each treatment and the cost (average cost or unit cost) for each type of HCRU will 
be reported separately, in 2018 values (or nearest value year). Due to differences in 
availability of data on costs for different types of HCRU in each country, such as 
administrative cost data or list prices, the methods used for calculating and (if relevant) 
inflating costs associated with each HRCU will be reported.

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HCRU and costs (Table 4) will be measured over the follow-up periods, as described at 9.2.3
section, however, the occurrence of any other effectiveness outcome or a safety outcome will 
not end the follow-up. The HCRU and cost of care outcomes will not be included in the meta-
analysis; instead, the HCRU and cost results will be reported descriptively by country.
Country-specific outcomes beyond this multi-country study
Country-specific primary and secondary outcomes can be included in the analyses, as 
specified in the localized protocols. The obtained results of such country-specific analyses on 
further outcomes will not be included in the combined results of the multi-country study
(ANNEX 3).

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Table 4
Master definitions for primary and secondary outcomes included in 
this study. 
Outcomes corresponding to
each objective
Definition1
Primary effectiveness outcomes
Primary outcome 1: 
Hospitalization for heart failure2
Definition 1a: Primary diagnosis3 associated with 
hospital admission 
Definition 1b: Any diagnosis2 associated with 
healthcare encounters, including hospitalizations and 
specialist outpatient and primary care encounters, or 
dispensation or any other record of the high-ceiling 
diuretics (loop diuretics).
Primary outcome 2: All-cause 
mortality
As available in the data sources
Primary outcome 3: Composite 
outcome including 
Hospitalization for heart failure2
All-cause mortality
As for primary outcome 1a and primary outcome 2
Primary outcome 4: Composite 
outcome including 
MI2
Stroke
All-cause mortality
For MI and stroke, any diagnosis2 associated with 
healthcare encounters, including hospitalizations and 
specialist outpatient and primary care encounters
For all-cause mortality, as for primary outcome 2
Secondary cardiovascular effectiveness outcomes
Secondary outcome 1: CV 
mortality
As available in the data sources
Secondary outcome 2: composite 
outcome including 
Hospitalization for heart failure2
CV mortality 
As for primary outcome 1a and secondary outcome 1.

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Table 4 (cont'd)
Master definitions for primary and secondary outcomes included in 
this study.
Outcomes corresponding to each 
objective
Definition1
Secondary cardiovascular effectiveness outcomes
Secondary outcome 3: 3-point 
MACE, a composite outcome 
including 
MI2
Stroke2
CV mortality
As for primary outcome 4 and secondary outcome 1.
Secondary outcome 4: Coronary 
revascularization procedure
Any diagnosis/procedure3 associated with healthcare 
encounters, including hospitalizations and specialist 
outpatient and primary care encounters
Secondary renal effectiveness outcomes
Secondary outcome 5: ESRD
Any diagnosis/procedure/laboratory measurement3
associated with healthcare encounters, including 
hospitalizations and specialist outpatient and 
primary care encounters
Secondary outcome 6: eGFR 
decline4
Definition 6a: Decline from normal kidney function 
(≥60ml/min/1,73m2) to abnormal kidney function 
(<60ml/min/1,73m2). 
Definition 6b: Change in eGFR over time. 
Secondary outcome 7: Progression 
from normoalbuminuria to micro-
or macroalbuminuria4
Progression from normoalbuminuria (<30mg/g) to 
micro- or macroalbuminuria (≥30mg/g).
Secondary outcome 8: Composite 
outcome including eGFR decline 
and progression to micro- or 
macroalbuminuria4
As for secondary outcome 6a and secondary 
outcome 7. 
Secondary safety outcomes
Secondary outcome 9: Bone 
fracture
Any diagnosis/procedure3 associated with healthcare 
encounters, including hospitalizations and specialist 
outpatient and primary care encounters

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Table 4 (cont'd)
Master definitions for primary and secondary outcomes included in 
this study.
Outcomes 
corresponding to each 
objective
Definition1
Secondary safety outcomes
Secondary outcome 10: 
Diabetic ketoacidosis
Any diagnosis3 associated with healthcare encounters, including 
hospitalizations and specialist outpatient and primary care encounters
Secondary outcome 11: 
Severe hypoglycemia
Any diagnosis3 associated with healthcare encounters, including 
hospitalizations and specialist outpatient and primary care encounters
Secondary outcome 12: 
Lower-limb amputation
Any diagnosis/procedure3 associated with healthcare encounters, 
including hospitalizations and specialist outpatient and primary care 
encounters
Secondary outcome 13 
Acute kidney injury 
requiring dialysis
Any diagnosis/procedure3 associated with healthcare encounters, 
including hospitalizations and specialist outpatient and primary care 
encounters
Secondary outcomes on HCRU and cost of care
Secondary outcome 14: 
HCRU
Outpatient healthcare visits
Primary care visits, specialist outpatient care visits or office visits, 
excluding emergency care, according to data availability
Emergency department visits 
Inpatient healthcare visits
Hospital admissions 
Inpatient days 
Length of stay 
Drug use in outpatient and inpatient care
Dispensations/other records of the drug use
Secondary outcome 15: 
Cost of care
Costs of HCRU (as in secondary outcome 14)
1 The outcome definitions shall be detailed in the localized protocols, using the master definitions presented in this master 
protocol; 2 As heart failure, MI and stroke are defined from diagnosis without mortality data, the outcomes include 
both fatal and non-fatal events; 3 Detailed variable definitions for the outcomes are available in ANNEX 6; 4 Based on 
the Kidney Disease Improving Global Outcomes (KDIGO) 2012 recommendations (ANNEX 6).
CV=cardiovascular; eGFR=estimated glomerular filtration rate; ESRD=end-stage renal disease; HCRU=health care resource 
utilization; MACE=major adverse cardiovascular event; MI=myocardial infarction.

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9.3.3
Covariates at baseline (baseline characteristics)
The types of covariates at baseline (baseline characteristics) utilized in this study and their 
measurement periods are listed in. Table 5. The complete list of covariates, representing each 
covariate type, and their operational definitions are available in ANNEX 7. The master 
definitions for the covariates presented in this master protocol shall be adapted to local
settings and described in the localized protocols, for country-level analyses (ANNEX 3).
Further, the availability of the covariates will vary between the data sources and will be 
specified in the localized protocols.
Additional covariates at baseline, or also during the follow-up, can be included in the 
additional country-specific analyses (ANNEX 3). The obtained results of such country-
specific analyses with additional covariates will not be included in the combined results of 
this multi-country study.
Table 5
Types of covariates at baseline.
Covariate1,2 at baseline
Measurement period
Sociodemographic characteristics
The index date (closest to)
Covariates related to lifestyle 
The index date (closest to)
Diabetes complications
12 months preceding the index date
(inclusive)
Other comorbidities
12 months preceding the index date
(inclusive)
Laboratory values
12 months preceding the index date
(inclusive)
Prior/concomitant use of other antidiabetic 
drugs
12 months preceding the index date and at 
the index date
Prior use of other drugs
12 months preceding the index date
(inclusive)
Healthcare resource utilization covariates
12 months preceding the index date
(inclusive)
Cost covariates
12 months preceding the index date
(inclusive)
The complete list of covariates, representing each covariate type, and their operational definitions are available in
ANNEX 7. These definitions shall be adapted to local settings and described in the localized protocols. The availability of
the variables shall also be specified in the localized protocols; 2 In the localized protocols, additional variables may be 
added.

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9.4
DATA SOURCES
This study will be based on several nationwide and regional data sources of observational 
data in 11 countries across Europe and Asia, namely Denmark, Finland, Germany, Israel, 
Japan, Norway, South Korea, Spain, Sweden, Taiwan, and the United Kingdom. This will 
ensure a sufficient number of drug users. Additional countries may be included during the 
course of the study.
Data sources eligible for this study include nationwide healthcare registers, regional quality 
registers, regional high-quality medical health records, and other health claims data. The 
utilized data sources, to be specified in the localized study protocols (ANNEX 3), will have a 
sufficient level of key data elements to successfully conduct the study. The key data elements 
in the utilized data sources will be the identification of patients using empagliflozin, any
SGLT-2 inhibitor, or any DPP-4 inhibitor and availability of patient-level data on exposures, 
outcomes, and covariates, including sociodemographic characteristics, other drugs, other 
diagnoses, and HCRU. Moreover, the utilized data sources shall be capable of delivering 
insights for the study in a reasonable timeframe, including consideration of data lag time and 
lag time due to administrative issues.
9.5
STUDY SIZE
Table 6 shows the sample size required to detect a 20% or 30% decrease in the outcome rate 
(HR 0.8 or 0.7, respectively) with 80% power and 5% alpha level. Varying expected outcome 
event rates (0.5-3% per patient-year) are presented assuming that each patient will contribute 
either 2 years, 1 year or 0.5 years of follow-up time. For example, in the EMPA-REG
OUTCOME® study [P18-01920] study the heart failure rate was approximately 1.5% per year 
in the non-empagliflozin arm, with HR = 0.65 for the empagliflozin arm.

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Table 6
The sample size required to detect 20% or 30% decrease (HR 0.80 or 
0.70) in the risk of outcome with 80% power as a function of yearly 
outcome event rate (ranging from 0.5% to 3.0%), and assuming either 
2.0, 1.0 or 0.5 years of average follow-up time.
Event rate
0.5%
1.0%
1.5%
2.0%
2.5%
3.0%
HR
0.80
0.80
0.80
0.80
0.80
0.80
Average follow-up time: 2.0 years
Sample required, 
per sub-cohort
35,000
18,000
12,000
9,000
7,000
6,000
Average follow-up time: 1.0 year
Sample required, 
per sub-cohort
71,000
35,000
24,000
18,000
14,000
12,000
Average follow-up time: 0.5 years
Sample required, 
per sub-cohort
142,000
71,000
47,000
35,000
28,000
24,000
Event rate
0.5%
1.0%
1.5%
2.0%
2.5%
3.0%
HR
0.70
0.70
0.70
0.70
0.70
0.70
Average follow-up time: 2.0 years
Sample required, 
per sub-cohort
15,000
7,000
5,000
4,000
3,000
2,000
Average follow-up time: 1.0 year
Sample required, 
per sub-cohort
30,000
15,000
10,000
7,000
6,000
5,000
Average follow-up time: 0.5 years
Sample required, 
per sub-cohort
60,000
30,000
20,000
15,000
12,000
10,000
HR=hazard ratio.
For example, with a baseline outcome rate of 1.5% per year, the analyses are sufficiently 
powered (>80%) to detect 30% decrease in the baseline rate with 20,000 patients per sub-
cohort, i.e., 40,000 patients in total, and 0.5 years of follow-up per patient.

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The estimated number of users of empagliflozin based on selected real-world datasets is 
presented in Table 7. The expected total number of patients in the study is at least over 
150,000, which is sufficient for most of the comparisons presented in. Table 6. However, the 
final power in the meta-analyses will also depend on the heterogeneity in the results across 
the study countries.
Table 7
The estimated number of empagliflozin users in selected databases by 
study country.
Country
N
Denmark
15,000
Finland
25,000
Germany
2,100
Israel
6,000
Japan
5,600
Norway
11,000
South Korea
39,000
Spain
12,000
Sweden
17,600
Taiwan
14,000
The United Kingdom
3,000-5,000

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9.6
DATA MANAGEMENT
9.6.1
Country-specific studies
Detailed data management procedures for the country-specific studies, including the used 
statistical software in each country, will be detailed in localized protocols (ANNEX 3). Each 
country will collect the variables from their data sources and comply with procedures that 
include checking electronic files, maintaining security and data confidentiality, following 
analysis plans, and performing quality checks for all programs. Each country will maintain 
any patient-identifying information securely on site according to up-to-date standard 
operating procedures. They will also maintain appropriate data storage, and archiving 
procedures will be followed with a periodic backup of files.
Each country will perform analyses with individual-level data separately as described in 
sections 9.7.1-9.7.6 (see also Figure 2). After performing the analyses with individual-level 
data in each country, aggregate-level results will be collected for combining the results from 
each country, in a pre-specified (similar) format to be detailed in the master statistical 
analysis plan (SAP). The master SAP will include template tables for collecting result data 
from each country.
9.6.2
A multi-country study combining country-specific results
After receiving the aggregate-level results from each country, the results will be combined by 
(see also Figure 2). The meta-analysis will be performed using the 
R language [R18-3507]. The aggregate-level results will be stored securely according to up-
to-date standard operating procedures. Maintaining appropriate data storage includes periodic 
backup of files and archiving procedures.
will comply with 
procedures that include checking electronic files, maintaining security and data 
confidentiality, following analyses plans, and performing quality checks for all programs. 
The source code of data management and data analyses is kept for inspection for five years 
after the publication of results. Access to the study data cannot be given to any third parties, 
neither the study data can be used for other purposes than described in this master protocol.

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9.7
DATA ANALYSIS
All analyses described in sections 9.7.1–9.7.6 will be performed separately by each country. 
Analyses for combining the country-specific results described in section 9.7.7 and 9.7.8 will 
be performed by 
Additional analyses, other than those described in this master protocol for the multi-country
study, may be detailed in localized study protocols (ANNEX 3). The obtained results of any 
additional analyses will not be included in the combined results of the multi-country study.
9.7.1
Propensity score methodology
PS matching will be used to reduce confounding in the comparative analyses across study 
sub-cohorts. Pairwise PS models between i) empagliflozin sub-cohort and DPP-4 sub-cohort 
and ii) SGLT-2 sub-cohort and DPP-4 sub-cohort will be estimated using logistic regression 
including all available covariates as indicated in ANNEX 7 (types of covariates are also 
outlined in Table 5). Propensity scores, obtained from the logistic regression models, indicate 
the predicted treatment probability of being in the main exposure sub-cohort, i.e. i) 
empagliflozin user or ii) any SGLT-2 inhibitor user.
 
PS matching will be done in a 1:1 ratio using the nearest-neighbor algorithm, using calipers 
of width equal to 0.2 of the standard deviation of the logit of the PS (matches of the main 
exposure sub-cohort and the comparator sub-cohort are formed if the caliper width is not 
exceeded for difference of the logits of PS). One-to-one matching will be used as one-to-
many matching introduces several complications while providing only a minimal gain in 
estimation precision [R17-1267].
In the matching procedure, matched comparator sub-cohort patients (any DPP-4 inhibitor 
sub-cohort) will be removed from the pool of eligible patients among the comparator sub-
cohort so that a matched patient is no longer available for consideration as a potential match 
for another exposed patient. If there are multiple potential matches (controls) available for a
patient in the main exposure sub-cohort (empagliflozin / any SGLT-2 inhibitor sub-cohort), 
then the controls will be sorted by (ascending) absolute difference in the logit of the PS, and 
the control on the top of this list will be selected. In case of a tie, the choice is made 
randomly.
Evaluation of the success of the matching procedure will be based on a standardized 
difference (detailed below) of a covariate between treatment groups. A standardized 
difference of a covariate of less than 0.1 between treatment groups in this study indicates a 
negligible difference in the mean or prevalence of the covariate. If larger standardized 
differences than 0.1 for some covariates exist after matching, they will be used in post-
matching adjustments (i.e. PS-variables with standardized difference >0.1 will be adjusted for 
in the analyses). Further adjustments can also be made as appropriate in additional models.

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The achieved PS balance will be investigated by plotting the PS-distribution and tabulating 
for each PS-variable the standardized difference among the main exposure sub-cohorts and 
the comparator sub-cohort. Standardized differences for the covariates included in the 
calculation of the PS will be calculated according to the unweighted formula provided by 
Austin [R18-3545]. The formula for standardized difference for a dichotomous covariate is:
 =
| −
|
(1 −) + 
(1 −
)
2
where  and 
 denote the prevalence in exposed and unexposed patients, respectively.
For a continuous variable the formula is:
 = |
 −
|


 + 

2
where 
 and 
 denote the sample means; 

 and 

 sample variances in exposed and 
unexposed patients, respectively. For a categorical variable with multiple levels, the method 
proposed by Dalton [R18-3515] will be used.
9.7.2
Baseline characteristics / descriptive statistics
For all included patients, descriptive statistics will be generated separately in each sub-cohort. 
Continuous covariates will be described by the mean, standard deviation (SD), median, 25th,
and 75th percentiles, minimum and maximum. Categorical covariates and continuous 
covariates that were also categorized will be described by proportion and frequency in each 
category. 
Patient characteristics at cohort entry for the main exposure sub-cohort and the comparator 
sub-cohort patients and the standardized differences before and after matching will be 
presented as in Table 8 below.

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Table 8
Illustration of baseline characteristics table. Among the main exposure sub-cohorts (empagliflozin/ SGLT-2 
inhibitor sub-cohort) and the comparator sub-cohort (DPP-4 sub-cohort), baseline characteristics variables will 
be presented before and after matching and their standardized differences. A separate table will be provided for 
the empagliflozin – any DPP-4 inhibitor sub-cohorts and the SGLT-2 inhibitor – any DPP-4 inhibitor sub-
cohorts.
Before matching
After matching
Main exposure 
sub-cohort
Comparator 
sub-cohort
Std. 
Main exposure 
sub-cohort
Comparator 
sub-cohort
Std.
Continuous variable 1 (e.g. age) that has been also categorized
Category 1 (e.g. <39 years) N 
(%)
n (p.pp)
n (p.pp)
-
n (p.pp)
n (p.pp)
-
Category 2 (e.g. 40-60 years) N 
(%)
n (p.pp)
n (p.pp)
-
n (p.pp)
n (p.pp)
-
Category 3 (e.g. >60 years) N 
(%)
n (p.pp)
n (p.pp)
-
n (p.pp)
n (p.pp)
-
Mean (SD)
Median (Q1, Q3)
Min, Max
x.xx (x.xx)
x.xx (x.xx, 
x.xx)
x.xx, x.xx
x.xx (x.xx)
x.xx (x.xx, 
x.xx)
x.xx, x.xx
x.xx
(based on 
mean)
x.xx (x.xx)
x.xx (x.xx, x.xx)
x.xx, x.xx
x.xx (x.xx)
x.xx (x.xx, 
x.xx)
x.xx, x.xx
x.xx
(based on 
mean)

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Table 8 (cont'd)
Illustration of baseline characteristics table. Among the main exposure sub-cohorts (empagliflozin/ SGLT-2 
inhibitor sub-cohort) and the comparator sub-cohort (DPP-4 sub-cohort), baseline characteristics variables will 
be presented before and after matching and their standardized differences. A separate table will be provided for 
the empagliflozin – any DPP-4 inhibitor sub-cohorts and the SGLT-2 inhibitor – any DPP-4 inhibitor sub-
cohorts.
Before matching
After matching
Main exposure 
sub-cohort
Comparator 
sub-cohort
Std. 
Main exposure 
sub-cohort
Comparator 
sub-cohort
Std.
Categorical variable 1 (e.g. 
sex)
Category 1 (e.g. male) N (%)
n (p.pp)
n (p.pp)
x.xx
n (p.pp)
n (p.pp)
x.xx
Category 2 (e.g. female) N (%)
n (p.pp)
n (p.pp)
-
n (p.pp)
n (p.pp)
-
Continuous variable 2 that has not been categorized
Mean (SD)
Median (Q1, Q3)
Min, Max
x.xx (x.xx)
x.xx (x.xx, 
x.xx)
x.xx, x.xx
x.xx (x.xx)
x.xx (x.xx, 
x.xx)
x.xx, x.xx
x.xx
(based on 
mean)
x.xx (x.xx)
x.xx (x.xx, x.xx)
x.xx, x.xx
x.xx (x.xx)
x.xx (x.xx, 
x.xx)
x.xx, x.xx
x.xx
(based on 
mean)
Std.=standardized difference; SD=standard deviations; Q1=first quartile; Q3=third quartile.

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The propensity score distributions (in logit scale) will be presented before and after matching 
as illustrated in Figure 8.
Figure 8
Illustration of propensity score distribution among the main exposure 
sub-cohorts (empagliflozin/ any SGLT-2 inhibitor sub-cohorts; 
“exposed” in the figure) and among the comparator sub-cohort (any 
DPP-4 inhibitor sub-cohort; “unexposed” in the figure) before and 
after matching. Separate figures will be provided for the 
empagliflozin – any DPP-4 inhibitor sub-cohorts and any SGLT-2 
inhibitor – any DPP-4 inhibitor sub-cohorts.
DPP-4=dipeptidyl peptidase-4; SGLT-2=sodium-glucose cotransporter-2.

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9.7.3
Primary effectiveness outcomes
Primary analyses
For the primary effectiveness outcomes, incidence rates (events per person-years) with 
corresponding 95% confidence intervals (CI) will be calculated, separately for each sub-
cohort. An example illustrating the result output is provided in Table 9. In addition, the 
competing risk-adjusted (i.e. treating death as competing event) cumulative incidence plots 
will be provided, and adjusted HRs with 95% CIs estimated using a Cox proportional hazard 
model. Components of all-cause mortality that are not part of the particular outcome will be 
considered as competing risk in the analyses of cumulative incidence. The cumulative 
incidence plots will be accompanied by a number of patients at risk at different time points 
during follow-up, as illustrated in Figure 9.
As described in section 9.7.1, the main Cox model will be adjusted for unbalanced PS-
variables at baseline. If there is a concern of residual confounding, analyses with further 
adjustments can be included in additional models to be detailed in localized study protocols. 
The possible additional models may include more adjusting covariates at baseline (also other 
than those included in ANNEX 7) and may include time-dependent exposures to drugs listed
in ANNEX 7. The obtained results of these additional models will not be included in the 
combined results of the multi-country study.
Table 9
The number of outcome events, patients at risk, incidence rates and 
hazard ratio with 95% confidence intervals among empagliflozin/any 
SGLT-2 inhibitor sub-cohort and among any DPP-4 inhibitor sub-
cohort.
Outcome: (e.g. heart
failure)
Any DPP-4
inhibitor sub-
cohort
Empagliflozin/Any SGLT-2 sub-
cohort
Events (person-years)
x.xx (y.yy)
x.xx (y.yy)
N at risk
N
N
Incidence rate (95% CI)
x.xx (x.xx)
x.xx (x.xx)
Adjusted HR (95% CI)
1 (reference)
x.xx (x.xx)
CI=confidence interval; DPP-4=dipeptidyl peptidase-4; HR=hazard ratio; SGLT-2=sodium-glucose cotransporter-2.

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Figure 9
Illustration of cumulative incidence plot. Death is treated as a 
competing event.
Alternative analyses with additional exclusion criteria
The primary analyses, as described above, will be re-performed using the following 
additional exclusion criteria: History of diagnosis of malignant neoplasm during the 5 years 
before the index date (ANNEX 8). Since applying this criterion will change the study 
population, the PS matching and balance analyses will also be re-performed.

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9.7.5
Secondary outcomes: effectiveness, safety, HCRU and costs of care
Effectiveness outcomes
The analysis of secondary outcomes 1-6a, 7, and 8 (Table 4) is done in a similar way as the 
analysis of primary effectiveness outcomes (section 9.7.3) and will be investigated for both 
empagliflozin and SGLT-2 inhibitor exposure.
The analyses for secondary outcomes 6a, 7, and 8 (Table 4) will be based on the PS-matched 
patients as described in section 9.7.1; however, additional exclusion criteria will be used 
(Figure 10). Persons with abnormal status at baseline will be excluded because no decline can 
be observed for those persons. Therefore, persons with eGFR<60 ml/min/1,73m2 will be 
excluded from analyses for secondary outcome 6a and 8. Similarly, persons with albuminuria 
level ≥30 mg/g will be excluded from analyses for secondary outcome 7 and 8. Persons with 
eGFR<30 ml/min/1,73m2 will be excluded from analyses for secondary outcome 6b. In 
addition, persons with no GFR measurements during the 12 months before (and including the 
date of) index date will be excluded from analyses regarding secondary outcomes 6-8. In the
analyses regarding secondary outcome 6b, persons who have measurements only during the 
first 4 weeks after the index date will be excluded (Figure 10). In all analyses for secondary 
outcomes 6-8, any measurements during the first 4 weeks after the index date will be 
disregarded (as described in Section 9.3.2).
Figure 10
Flow chart for secondary renal effectiveness outcomes
PS=propensity score; GFR=glomerular filtration rate; eGFR=estimated glomerular filtration rate

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Regarding secondary outcome 6a, 7 and 8, the number and proportion of patients who stay 
or move to the lower/higher eGFR/albuminuria state between the baseline and the last 
available measurement will be summarized in a N x N table (where N is the number of 
possible states (Figure 10). Each study cohort will be described separately. In this table all 
patients in the matched cohort will be included, regardless of missing values or abnormal 
states at baseline or at last available measurement.
Regarding secondary outcome 6b (Table 4), the population trend for the change of eGFR 
will be characterized by sub-cohorts using moving averages over time. Specifically, the mean 
values overall patients with existing measurements will be calculated in three-month 
windows starting with four weeks after the index date, securing the lag period. Each patient 
contributes equally within the time-window, meaning that patients with more than one 
measurement within the time-window will contribute with the mean value of their 
measurements. The percentage of patients having at least one measure will be calculated for 
each time-window. The trends will be visualized by sub-cohorts as illustrated in Figure 11.
Figure 11
Illustration of the eGFR change by sub-cohort.
eGFR=estimated glomerular filtration rate

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Further, the slope of eGFR change (average change per unit time: (observed value in time-
window – baseline value)/time(years)) between the baseline eGFR and the last measured 
value within pre-fixed time-window will be compared between sub-cohorts using linear 
regression model adjusted for baseline eGFR value and variables not balanced after PS 
matching. The following time-windows will be used:

from the start of week 5 until the end of follow-up (AT approach),

from the start of week 5 until the end of 12 months or the end of follow-up 
(whichever comes first) and will include 3 month-interval analysis if sufficient sample 
sizes exist

from the start of 13th month until the end of 24 months or the end of follow-up 
(whichever comes first)

moving along yearly until the end of data availability
The follow-up is not censored in the occurrence of an effectiveness or safety outcome. All 
patients with baseline eGFR >30 ml/min/1,73m2 and at least 1 measurement in the 
corresponding time-window will be included in the analyses. The regression coefficients will 
be presented together with 95% CIs. In country-specific analyses, alternative methods (e.g. 
mixed effect models) can be used in case of sufficient data availability. These country-
specific results will not be included in the meta-analysis.
When excluding patients from the analyses of outcomes 6a, 6b, 7 and 8, the same matched 
cohort that will be used for primary and other secondary outcomes, will be used, i.e. no re-
matching will be done. Instead, to ensure balance across cohorts, when excluding patients 
from the exposed sub-cohort, the corresponding matched control will also be excluded. 
Similarly, when excluding patients from the unexposed, the corresponding matched exposed 
patient will also be excluded. After this, the balance will be checked, and the unbalanced 
variables will be adjusted for in the analyses.
Safety outcomes
The safety outcomes will be investigated for empagliflozin exposure only. In cases where the 
follow-up is censored at discontinuation of drug use, the exposure risk window (Figure 7) 
will be accounted for. 
The analysis of safety outcomes will include the description of the number of outcome 
events, patients at risk, incidence rates with the 95% CIs, and cumulative incidence function 
plots for the safety outcomes. All-cause mortality will be considered as a competing risk in 
the analyses of cumulative incidence.
The HRs together with the 95% CIs will be estimated by Cox regression for all time-to-event 
outcomes. The HRs will be estimated using models adjusted for the unbalanced PS-variables 
at baseline, as described in section 9.7.1. All safety outcomes will be analyzed with the time-
to-event approach.

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In the multi-country study, the main approach in the analyses of safety outcomes is to study 
the time to the first event. In country-specific analyses, recurrent safety outcomes can be 
considered, as described in local SAPs. These country-specific analyses will not be included 
in the meta-analyses.

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Table 10
Description of transitions between eGFR and albuminuria states from baseline to the last available 
measurement.
At baseline
At last measurement
Missing data
Sub-cohort*:
eGFR 1
albuminur
ia 1
eGFR 1
albuminur
ia 0
eGFR 0
albuminur
ia 1
eGFR 0
albuminur
ia 0
eGFR 0
albuminur
ia 2
eGFR 2
albuminur
ia 0
eGFR 1
albuminur
ia 2
eGFR 2
albuminur
ia 1
eGFR 2
albuminur
ia2
eGF
R
albu
.
N
1
1
N
11
n1111
(%**)
n1110
(%)
n1101
(%)
n1100
(%)
n1102
n1120
n1112
n1121
n1122
1
0
N
10
n1011
(%)
n1010
(%)
n1001
(%)
n1000
(%)
n1002
n1020
n1012
n1021
n1022
0
1
N
01
n0111
(%)
n0110
(%)
n0101
(%)
n0100
(%)
n0102
n0120
n0112
n0121
n0122
0
0
N
00
n0011
(%)
n0010
(%)
n0001
(%)
n0000
(%)
n0002
n0020
n0012
n0021
n0022
0
2
N
02
n0211
n0210
n0201
n0200
n0202
n0220
n0212
n0221
n0222
2
0
N
20
n2011
n2010
n2001
n2000
n2002
n2020
n2012
n2021
n2022
1
2
N
12
n1211
n1210
n1201
n1200
n1202
n1220
n1212
n1221
n1222

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Table 10 (cont'd)
Description of transitions between eGFR and albuminuria states from baseline to the last available 
measurement.
At baseline
At last measurement
Missing data
Sub-cohort*:
eGFR 1
albuminur
ia 1
eGFR 1
albuminur
ia 0
eGFR 0
albuminur
ia 1
eGFR 0
albuminur
ia 0
eGFR 0
albuminur
ia 2
eGFR 2
albuminur
ia 0
eGFR 1
albuminur
ia 2
eGFR 2
albuminur
ia 1
eGFR 2
albuminur
ia2
eGF
R
albu
.
N
2
1
N2
1
n2111
n2110
n2101
n2100
n2102
n2120
n2112
n2121
n2122
2
2
N2
2
n2211
n2210
n2201
n2200
n2202
n2220
n2212
n2221
n2222
* This table will be presented for all sub-cohorts (Empagliflozin/SGLT-2/DPP-4); 
**The denominators for the percentages calculations will be the numbers from the third column (N11,N10,etc)
eGFR=estimated glomerular filtration rate; albu.= albuminuria;
0=abnormal; 1=normal; 2=missing.

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HCRU outcomes
The HCRU outcomes (Table 4) will be investigated for empagliflozin exposure only. HCRU 
outcomes will be analyzed separately in each sub-cohorts, i.e. empagliflozin and DPP-4
inhibitors, by using the AT approach, applying the specific reasons for ending the follow-up 
(see section 9.3.2). Only time observed during follow-up will be considered in the analyses,
although inpatient stays may extend outside the study period. For example, when reporting 
the length of inpatient stay in the case a patient is admitted before the end of a study period, 
but not discharged until its end, the days going past the end of the study period will not be 
considered (right truncation). The same procedure will be applied when calculating outcomes 
per member per month and a hospital stay extends over different monthly windows.
The total number of inpatient days will be counted and reported for each patient during 
follow-up. The mean, standard deviation, median, 25th, and 75th quartiles, minimum, and 
maximum will be reported for the crude number of inpatient days per patient, and as the 
proportion of inpatient days per each patient´s follow-up time. The number of inpatient days 
will also be calculated and reported per member per month.
For outpatient healthcare visits, inpatient healthcare visits and drug use (Table 4), the number 
of events (total), person-years, and incidence rates (number of events per person-year) will be 
calculated and reported. Each of these three resource utilization types will be analyzed 
separately. A total number of inpatient visits, outpatient visits, and dispensations or any other 
records of the drug use (each separately) will be compared across treatment groups using a 
Poisson regression model. The logarithm of follow-up time will be used as an offset in the 
model. However, if the Poisson assumptions are violated, another modeling option can be 
used (e.g. zero-inflated model or negative-binomial). When counting the number of events 
and person-years for healthcare visits, inpatient days will be censored (i.e. not counted as risk 
time). The number of visits will also be calculated and reported per member per month.
The first inpatient visit (hospitalization) will be analyzed separately by reporting the number 
of events, person-time, and incidence rate. Further, HRs with 95% confidence intervals will 
be estimated using the Cox proportional hazard models, comparing treatment groups and 
adjusting for unbalanced PS-variables. In this analysis, time after the first hospitalization will 
be censored.
As described in section 9.7.1, the main Cox and Poisson models will be adjusted for 
unbalanced PS-variables at baseline. In addition, as the event rate can increase as a function 
of time since the start of follow-up, year of follow-up will be additionally adjusted for.
In country-specific analyses, HCRU outcomes can be additionally analyzed separately by 
type: e.g. CV vs. non-CV, diabetes-related vs. non-diabetes related resources.
Cost of care outcomes
The cost of care outcomes (Table 4) will be investigated for empagliflozin exposure only. 
Cost of care outcomes will be analyzed separately in each sub-cohorts, i.e. empagliflozin and 
DPP-4 inhibitors, by using the AT approach, applying the specific reasons for ending the 
follow-up (see section 9.3.2).

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Costs will be reported overall and separately based on the type of service: inpatient healthcare 
visits, outpatient healthcare visits, and drug use (Table 4). For the primary analysis of cost 
outcomes, the Lin’s method will be applied [R17-2088]. Specifically, the average cost 
accrued per member in a given month (i.e. cost per member per month) will be estimated. 
This involves calculating the average cost among members who are alive at the beginning of 
a month. Cost per member per month then will be weighted by Kaplan-Meier probability of 
survival for each month and then summed up over available months of the study period.
Poisson regression will also be used to estimate the relationship between total costs and 
treatment (empagliflozin vs. any DPP-4 inhibitor), controlling for patient covariates. For the 
regression analyses, patients’ observed costs within each month will be weighted by inverse 
probability of not being censored, due to potential informative censoring [R18-3512]. After 
weighting, the formal comparison of secondary cost outcomes between study sub-cohorts will 
be done by estimating rate ratios using the Poisson regression with 95% CI, adjusting for 
potential confounders. The logarithm of follow-up time will be used as an offset in the model. 
However, if the Poisson assumptions are violated, another modeling option can be used (e.g. 
zero-inflated model, negative-binomial, other link function with or without data 
transformation).
As described in section 9.7.1, the main Poisson models will be adjusted for unbalanced PS-
variables at baseline. In addition, as the event rate can increase as a function of time since the 
start of follow-up, year of follow-up will be additionally adjusted for.
In country-specific analyses, cost outcomes can be additionally analyzed separately by type: 
e.g. CV vs. non-CV, diabetes-related vs. non-diabetes related costs. The obtained results of 
these additional analyses will not be included in the combined results of the multi-country
study.

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9.7.7
Combining effectiveness results from countries: meta-analyses
Meta-analyses will be performed for the primary and secondary effectiveness outcomes and 
the safety outcomes, to combine individual country-level results. In the main meta-analyses,
all countries will be included. In additional analyses, several subgroups of countries (e.g. 
Nordic, European, and Asian countries separately) will be included.
Prior to conducting meta-analyses, heterogeneity across the countries in terms of study design 
and conduct will be assessed by considering deviations from this master protocol for each 
country. Specifically, the variability in population characteristics (including data availability), 
study design and statistical methods used will be investigated. Statistical heterogeneity will 
be subsequently assessed using:
-
The estimated total heterogeneity.
-
The Chi-squared test (significance level: 0.1).
-
I2 statistic (0% to 40%: might not be important; 30% to 60%: may represent moderate 
heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: 
considerable heterogeneity).
If high levels of heterogeneity exist (I2 >=50% or P<0.1), the study design and characteristics 
in the included country-specific studies will be reviewed and the possible source of 
heterogeneity discussed. Additional meta-analyses may also be performed excluding 
countries leading to high heterogeneity.
Results of the meta-analyses will be derived using a random-effects model, and will be 
presented in a forest plot including the following information:
-
Study identifiers.
-
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 HR with 95% CI (on a log scale).
-
The estimated amount of heterogeneity.
-
Value of the Chi2 test statistic, with the number of degrees of freedom and p-value.
-
The proportion of variability explained by heterogeneity (I2).
-
The value of the Z score for overall effect with the p-value.
An example figure is given below in Figure 12

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Figure 12
Illustration of meta-analysis results.
CI=confidence interval.
9.7.8
Presenting the HCRU and cost of care results from countries descriptively
HCRU and cost of care outcomes (Table 4) will be presented descriptively by country, but 
not combined by meta-analysis methods.
9.7.9
Adjustment for multiple comparisons
Will not be applied.
9.8
QUALITY CONTROL
9.8.1
Country-specific studies: localized protocols, localized SAPs, country-specific
analyses, and country-specific study reports
Each study country will localize this master protocol (Figure 2). For the localized protocols, 
localized SAPs, country-specific analyses, and country-specific study reports, quality control 
procedures will be described in each localized protocol.
9.8.2
Multi-country study: master protocol, master SAP, analyses with aggregate-
level results from the countries, and final report
Master protocol, master SAP, and multi-country report
All key study documents of the multi-country study, the master protocol, the master SAP, and 
the multi-country report will undergo quality-control review, senior scientific review, and 
editorial review.
The study will be conducted as specified in this master protocol. The principal investigator, 
the co-investigators and the sponsors of the study must approve all revisions to the master 
protocol. All changes are documented as master protocol amendments.

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This master protocol has been written following the Code of Conduct by the European 
Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) [R18-
3511]. The protocol also follows the key elements of the Guideline for Good 
Pharmacoepidemiology Practices by International Society for Pharmacoepidemiology.
 the principal investigator, co-investigators, the Sponsors and 
individuals acting on their behalf commit to adhere to the rules of the ENCePP Code of 
Conduct in their entirety.
Multi-country analyses: combining the country-specific results
For the multi-country analyses,
will receive aggregate-level data 
from each country, to be combined. Standard operating procedures of 
will be used in the conduct of the combined multi-country analyses, including the
meta-analysis and presenting results descriptively. These procedures include internal quality 
audits, rules for secure and confidential data storage, methods to maintain and archive project 
documents, and quality control procedures for programming. All work for the multi-country
analyses will be subject to quality control and documentation procedures to make certain the 
multi-country report is accurate and thorough, and the multi-country analyses can be 
reproduced. If the data do not permit the meta-analysis as planned or if clarifying analyses are 
required, the missing or the additional information and results will be included in the multi-
country report and the corresponding explanation given.
Quality control will also be performed on the retrieved aggregate data from each country, 
including controlling the inclusion of necessary results from each country. If data are missing 
or incorrect, the dataset is sent back to the local contract points for correction.
All programs for data management and data analyses for the combined multi-country
analyses will be written by the 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.
9.9
LIMITATIONS OF THE RESEARCH METHODS
9.9.1
Data sources and variables
As this study will incorporate data sources from several countries, the availability, coverage, 
and validity of information will vary. For example, laboratory values will not be available in 
all countries, limiting the investigation of renal effectiveness outcomes. Further, the available 
laboratory values might be affected by information bias, if measurements are 
disproportionally frequently available for patients with decreased renal function. There will 
also be limitations specific to each data source. Some data sources might provide samples
that have been selected on the basis of, for example, income status and capability to use 
healthcare services.

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9.9.2
Identifying patients with T2DM
The validity of T2DM diagnoses will vary between countries due to varying recording 
practices. However, the participating countries shall define the most appropriate strategy of 
identifying patients with T2DM from the utilized data sources. The beginning of T2DM 
symptoms cannot be determined from the utilized data sources, whereas the date of diagnosis 
usually can be determined. Therefore, the duration of the disease cannot be determined.
9.9.3
Drug exposure
Secondary data sources do not include information on actual drug use patterns and, therefore, 
the drug exposure in this study may be misclassified. Further, the data sources might not 
include complete information on drug dispensations or other records of drug use. Prescription 
data is one further potential source for exposure misclassification as the dispensation date 
cannot be determined.
The drugs of interest are relatively new, and the available follow-up data will be limited to up 
to approximately six years for SGLT-2 inhibitors and up to approximately four years for 
empagliflozin (as clarified in section 9.2.1).
9.9.4
Bias and confounding
Confounding by indication cannot be completely excluded from this study although several 
approaches will be used to minimize confounding (section 9.12). Further, there will be 
residual confounding related to, for example, incomplete recording of diagnoses and potential 
lack of variables in the data sources to be utilized.
9.9.5
Analyses
This will be an observational study and, therefore the results will indicate a correlation 
between drug use and selected outcomes. Causality cannot be determined in observational 
studies. Potential heterogeneity in the results provided by the countries will be addressed with 
the random-effects model.
9.10
OTHER ASPECTS
None specified. 
9.11
SUBJECTS
Not applicable as this is a cohort study.
9.11.1
Cases
Not applicable as this is a cohort study.
9.11.2
Controls
Not applicable as this is a cohort study.

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9.12
BIAS
This study will include new users of empagliflozin, any SGLT-2 inhibitor, and any DPP-4 
inhibitor. Immortal time bias [P07-06047] will be minimal as the follow-up will begin at the 
initiation of drug use. Adherence to drug use will be unknown. Potential bias from exposure 
misclassification will be addressed with grace periods and the ITT analyses.
Comparing the outcomes between users of empagliflozin/any SGLT-2 inhibitor and any 
DPP-4 inhibitor will decrease confounding by indication, as the comparison group will have a 
similar indication to drug use than the patients in the empagliflozin/SGLT-2 sub-cohorts 
[R18-3506]. 
 
 
The compared sub-cohorts will be matched on the basis of PS. The PS will be computed on 
the basis of a wide range of covariates related to sociodemographic characteristics, lifestyle, 
diabetes complications, other comorbidities, laboratory values, prior/concomitant use of other 
antidiabetic drugs, prior/concomitant use of other drugs, healthcare resource utilization 
covariates, and cost covariates. The PS matching will decrease the systematic differences 
between the sub-cohorts and, thus, decrease confounding.
10.
PROTECTION OF HUMAN SUBJECTS
Per design, this non-interventional study utilizes secondary data. Thus, the study does not 
affect the treatment or health outcomes of the study individuals. The study individuals will 
not be contacted in any phase of the study.
10.1
COUNTRY-SPECIFIC STUDIES
For the country-specific studies, each localized protocol will detail the protection of human 
subjects, including applicable applications for ethical approval and data protection according 
to national legislation.
10.2
MULTI-COUNTRY STUDY
For the multi-country study
 will receive exclusively aggregate-level
results from each country, in which study individuals in the countries cannot be identified. 
 will not have access to the individual-level data at any time of the 
study. Thus, no ethical approval is required for the multi-country study.
11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
Not applicable. Data is anonymized, extracted, analyzed, validated and reported in aggregate.
There is no potential that any employee of BI or agent working on behalf of BI will access 
individual patient data in which the patient may be identified during data compilation, data 
reporting or data analysis.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
Manuscripts describing this work will be submitted for publication in peer-review journals. 
Results may also be submitted for presentation at scientific conferences.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
P07-06047
Suissa S. Immortal time bias in observational studies of drug effects. 
Pharmacoepidemiol Drug Saf 2007;16:241–9. doi:10.1002/pds.1357
P15-09840
Association AD. Pharmacologic Approaches to Glycemic Treatment: 
Standards of Medical Care in Diabetes—2018. Diabetes Care 2018;41:S73–
85. doi:10.2337/dc18-S008
P17-01701
Hsia DS, Grove O, Cefalu WT. An update on sodium-glucose co-transporter-2 
inhibitors for the treatment of diabetes mellitus. Curr Opin Endocrinol 
Diabetes Obes 2017;24:73–9. doi:10.1097/MED.0000000000000311
P17-05895
Kosiborod M, Cavender MA, Fu AZ, et al. Lower Risk of Heart Failure and 
Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors 
Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative 
Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose 
Cotransporter-2 Inhibitors). Circulation 2017;136:249–59. 
doi:10.1161/CIRCULATIONAHA.117.029190
P17-08964
Birkeland KI, Jørgensen ME, Carstensen B, et al. Cardiovascular mortality and 
morbidity in patients with type 2 diabetes following initiation of sodium-
glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-
REAL Nordic): a multinational observational analysis. Lancet Diabetes 
Endocrinol 2017;5:709–17. doi:10.1016/S2213-8587(17)30258-9
P18-01920
Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular 
Outcomes, and Mortality in Type 2 Diabetes. New England Journal of 
Medicine 2015;373:2117–28. doi:10.1056/NEJMoa1504720
P18-02804
Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular 
and Renal Events in Type 2 Diabetes. New England Journal of Medicine 
2017;377:644–57. doi:10.1056/NEJMoa1611925
P18-04466
Scheen AJ. Cardiovascular Effects of New Oral Glucose-Lowering Agents: 
DPP-4 and SGLT-2 Inhibitors. Circ Res 2018;122:1439–59. 
doi:10.1161/CIRCRESAHA.117.311588
P18-06283
Kosiborod M, Lam CSP, Kohsaka S, et al. Cardiovascular Events Associated 
With SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-
REAL 2 Study. J Am Coll Cardiol 2018;71:2628–39. 
doi:10.1016/j.jacc.2018.03.009
P18-09763 
Wanner C, Heerspink H, Zinman B, et al. Empagliflozin and Kidney Function 
Decline in Patients with Type 2 Diabetes: A Slope Analysis from the EMPA-
REG OUTCOME Trial. J Am Soc Nephrol 2018;29:2755–69. 
doi:10.1681/ASN.2018010103
P18-10828
International Diabetes Federation. IDF Clinical Practice Recommendations for 
managing Type 2 Diabetes in Primary Care. 
2017.https://www.idf.org/component/attachments/attachments.html?id=1270&
task=download (accessed 25 Sep 2018).
P18-10986
Ueda P, Svanström H, Melbye M, et al. Sodium glucose cotransporter 2 
inhibitors and risk of serious adverse events: nationwide register based cohort 
study. BMJ 2018;363. doi:10.1136/bmj.k4365

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P19-04731 
Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular 
Outcomes in Type 2 Diabetes. New England Journal of Medicine 
2019;380:347–57. doi:10.1056/NEJMoa1812389
R13-4387
Kidney International Supplements | KDIGO 2012 Clinical Practice Guideline 
for the Evaluation and Management of Chronic Kidney Disease | 
ScienceDirect.com. https://www.sciencedirect.com/journal/kidney-
international-supplements/vol/3/issue/1 (accessed 13 Mar 2019)
R15-1988
Chen L, Magliano DJ, Zimmet PZ. The worldwide epidemiology of type 2 
diabetes mellitus—present and future perspectives. Nature Reviews 
Endocrinology 2012;8:228–36. doi:10.1038/nrendo.2011.183
R17-1267
Wang SV, Schneeweiss S, Rassen JA. Optimal Matching Ratios in Drug 
Safety Surveillance: Epidemiology 2014;25:772–3. 
doi:10.1097/EDE.0000000000000148
R17-2088
Lin DY, Feuer EJ, Etzioni R, et al. Estimating medical costs from incomplete 
follow-up data. Biometrics 1997;53:419–34.
R18-3505
Persson F, Nyström T, Jørgensen ME, et al. Dapagliflozin is associated with 
lower risk of cardiovascular events and all-cause mortality in people with type 
2 diabetes (CVD-REAL Nordic) when compared with dipeptidyl peptidase-4 
inhibitor therapy: A multinational observational study. Diabetes Obes Metab 
2018;20:344–51. doi:10.1111/dom.13077
R18-3506
Lund JL, Richardson DB, Stürmer T. The active comparator, new user study 
design in pharmacoepidemiology: historical foundations and contemporary 
application. Curr Epidemiol Rep 2015;2:221–8. doi:10.1007/s40471-015-
0053-5
R18-3507
R Core Team. R: A language and environment for statistical computing. R 
Foundation for Statistical Computing, Vienna, Austria. URL http://www.R-
project.org/
К18-3508
Лфтп НЬб Лшь Н-Об Зфкл О-Нб уе фдю Mortality and causes of death in a 
national sample of type 2 diabetic patients in Korea from 2002 to 2013. 
Cardiovascular Diabetology 2016;15:131. doi:10.1186/s12933-016-0451-0
R18-3509
Einarson TR, Acs A, Ludwig C, et al. Economic Burden of Cardiovascular 
Disease in Type 2 Diabetes: A Systematic Review. Value Health;21:881–90. 
doi:10.1016/j.jval.2017.12.019
R18-3510
Einarson TR, Acs A, Ludwig C, et al. Prevalence of cardiovascular disease in 
type 2 diabetes: a systematic literature review of scientific evidence from 
across the world in 2007-2017. Cardiovasc Diabetol 2018;17:83. 
doi:10.1186/s12933-018-0728-6
R18-3511
ENCePP. Code of Conduct. www.encepp.eu/code_of_conduct/ (accessed 13 
May 2015).
R18-3512
Huang Y. Cost analysis with censored data. Med Care 2009;47:S115-119. 
doi:10.1097/MLR.0b013e31819bc08a
R18-3515
Dongsheng Yang, Jarrod E. Dalton. A unified approach to measuring the 
effect size between two groups using SAS. 
http://support.sas.com/resources/papers/proceedings12/335-2012.pdf
R18-3545
Austin PC. Assessing balance in measured baseline covariates when using 
many-to-one matching on the propensity-score. Pharmacoepidemiology and 
Drug Safety 2008;17:1218–25. doi:10.1002/pds.1674

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13.2
UNPUBLISHED REFERENCES
Not applicable

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
c26457869-01 Multi-country non-interventional study on the effectiveness of Empagliflozin 
in adult patients with type 2 diabetes in Europe and Asia; version 1.0; 29 November 2018 

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Study title: Multi-country non-interventional study on the effectiveness and safety of Empagliflozin in adult 
patients with type 2 diabetes in Europe and Asia
EU PAS Register® number: EUPAS27606
Study reference number (if applicable): 1245.195 (sponsor study number)
Section 1: Milestones
Yes
No
N/A
Section 
Number
1.1
Does the protocol specify timelines for 
1.1.1 Start of data collection5
6
1.1.2 End of data collection6
6
1.1.3 Progress report(s)
1.1.4 Interim report(s)
6
1.1.5 Registration in the EU PAS Register®
6
1.1.6 Final report of study results.
6.0
Comments:
Progress reports are not conducted in this study, only interim reports.
Section 2: Research question
Yes
No
N/A
Section 
Number
2.1
Does the formulation of the research question and 
objectives clearly explain: 
2.1.1 Why the study is conducted? (e.g. to address an 
important public health concern, a risk identified in the 
risk management plan, an emerging safety issue)
7
2.1.2 The objective(s) of the study?
8
2.1.3 The target population? (i.e. population or subgroup to 
whom the study results are intended to be generalised)
9.2.2
2.1.4 Which hypothesis(-es) is (are) to be tested?
8, 9.7
2.1.5 If applicable, that there is no a priori hypothesis?
Comments:
Section 3: Study design
Yes
No
N/A
Section 
Number
3.1
Is the study design described? (e.g. cohort, case-control, 
cross-sectional, other design) 
9.1
3.2
Does the protocol specify whether the study is based on 
primary, secondary or combined data collection?
9.1
                                                
5 Date from which information on the first study is first recorded in the study dataset or, in the case of secondary use of data, 
the date from which data extraction starts.
6 Date from which the analytical dataset is completely available.

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Section 3: Study design
Yes
No
N/A
Section 
Number
3.3
Does the protocol specify measures of occurrence? 
(e.g., rate, risk, prevalence)
8
3.4
Does the protocol specify measure(s) of association? 
(e.g. risk, odds ratio, excess risk, rate ratio, hazard ratio, 
risk/rate difference, number needed to harm (NNH))
9.7
3.5
Does the protocol describe the approach for the collection 
and reporting of adverse events/adverse reactions? 
(e.g. adverse events that will not be collected in case of 
primary data collection)
11
Comments:
Section 4: Source and study populations
Yes
No
N/A
Section 
Number
4.1
Is the source population described?
9.2.1
4.2
Is the planned study population defined in terms of:
4.2.1 Study time period
9.2.1
4.2.2 Age and sex
9.2.2
4.2.3 Country of origin
9.2.1
4.2.4 Disease/indication
9.2.2
4.2.5 Duration of follow-up
9.2.3
4.3
Does the protocol define how the study population will be 
sampled from the source population? (e.g. event or 
inclusion/exclusion criteria)
9.2.2
Comments:
Section 5: Exposure definition and measurement
Yes
No
N/A
Section 
Number
5.1
Does the protocol describe how the study exposure is 
defined and measured? (e.g. operational details for defining 
and categorising exposure, measurement of dose and 
duration of drug exposure)
9.2.3
9.3.1
5.2
Does the protocol address the validity of the exposure 
measurement? (e.g. precision, accuracy, use of validation 
sub-study)
5.3
Is exposure categorised according to time windows? 
9.3.1
5.4
Is intensity of exposure addressed?
(e.g. dose, duration)
9.3.1
5.5
Is exposure categorised based on biological mechanism of 
action and taking into account the pharmacokinetics and 
pharmacodynamics of the drug?
5.6
Is (are) (an) appropriate comparator(s) identified?
9.3.1
Comments:

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Section 6: Outcome definition and measurement
Yes
No
N/A
Section 
Number
6.1
Does the protocol specify the primary and secondary (if 
applicable) outcome(s) to be investigated?
9.3.2
6.2
Does the protocol describe how the outcomes are defined 
and measured? 
9.3.2
6.3
Does the protocol address the validity of outcome 
measurement? (e.g. precision, accuracy, sensitivity, 
specificity, positive predictive value, use of validation sub-
study)
6.4
Does the protocol describe specific outcomes relevant for 
Health Technology Assessment? (e.g. HRQoL, QALYs, 
DALYs, health care services utilisation, burden of disease 
or treatment, compliance, disease management)
9.3.2
9.7.5
Comments:
Section 7: Bias
Yes
No
N/A
Section 
Number
7.1
Does the protocol address ways to measure confounding? 
(e.g. confounding by indication)
9.7, 
9.9.4
9.12
7.2
Does the protocol address selection bias? (e.g. healthy 
user/adherer bias)
7.3
Does the protocol address information bias? 
(e.g. misclassification of exposure and outcomes, time-
related bias)
9.7,
9.9.3
9.12
Comments:
Section 8: Effect measure modification
Yes
No
N/A
Section 
Number
8.1
Does the protocol address effect modifiers? (e.g. collection 
of data on known effect modifiers, sub-group analyses, 
anticipated direction of effect) 
9.3.3
9.3.4,
9.7
Comments:
Section 9: Data sources
Yes
No
N/A
Section 
Number
9.1
Does the protocol describe the data source(s) used in the 
study for the ascertainment of:
9.1.1 Exposure? (e.g. pharmacy dispensing, general practice 
prescribing, claims data, self-report, face-to-face 
interview)
9.4

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Section 9: Data sources
Yes
No
N/A
Section 
Number
9.1.2 Outcomes? (e.g. clinical records, laboratory markers 
or values, claims data, self-report, patient interview 
including scales and questionnaires, vital statistics)
9.4
9.1.3 Covariates and other characteristics?
9.4
9.2
Does the protocol describe the information available from 
the data source(s) on:
9.2.1 Exposure? (e.g. date of dispensing, drug quantity, 
dose, number of days of supply prescription, daily 
dosage,prescriber)
9.2.2 Outcomes? (e.g. date of occurrence, multiple event, 
severity measures related to event)
9.2.3 Covariates and other characteristics? (e.g. age, sex, 
clinical and drug use history, co-morbidity, co-
medications, lifestyle)
9.3
Is a coding system described for: 
9.3.1 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC) Classification System)
9.3.1
9.3.2 Outcomes? (e.g. International Classification of 
Diseases (ICD), Medical Dictionary for Regulatory 
Activities (MedDRA))
9.3.2
9.3.3 Covariates and other characteristics?
9.3.3
Annex 7
9.4
Is a linkage method between data sources described? 
(e.g. based on a unique identifier or other) 
Comments:
Questions 9.2 and 9.4: The utilized data sources and linkage methods will be further specified and described 
in the localized study protocols.
Section 10: Analysis plan
Yes
No
N/A
Section 
Number
10.1
Are the statistical methods and the reason for their choice 
described? 
9.3.1
9.7
10.2
Is study size and/or statistical precision estimated?
9.5
10.3
Are descriptive analyses included?
9.7.2
10.4
Are stratified analyses included?
9.7.3-9.7.6
10.5
Does the plan describe methods for analytic control of 
confounding?
9.7
10.6
Does the plan describe methods for analytic control of 
outcome misclassification?
10.7
Does the plan describe methods for handling missing data?
9.8.2
10.8
Are relevant sensitivity analyses described?
9.7.4
9.7.6
Comments:

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Section 11: Data management and quality control
Yes
No
N/A
Section 
Number
11.1
Does the protocol provide information on data storage? 
(e.g. software and IT environment, database maintenance 
and anti-fraud protection, archiving)
9.6
11.2
Are methods of quality assurance described?
9.8
11.3
Is there a system in place for independent review of study 
results? 
Comments:
Questions 11.1 and 11.2: The country-specific data management and quality control measures will be further 
specified and described in the localized study protocols.
Section 12: Limitations
Yes
No
N/A
Section 
Number
12.1
Does the protocol discuss the impact on the study results of:
12.1.1 Selection bias?
12.1.2 Information bias?
9.9.4
12.1.3 Residual/unmeasured confounding?
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods).
9.9.4, 9.7.7
12.2
Does the protocol discuss study feasibility? (e.g. study size, 
anticipated exposure uptake, duration of follow-up in a 
cohort study, patient recruitment, precision of the estimates)
9.5.
Comments:
Section 13: Ethical/data protection issues
Yes
No
N/A
Section 
Number
13.1
Have requirements of Ethics Committee/ Institutional 
Review Board been described?
10.1, 10.2
13.2
Has any outcome of an ethical review procedure been 
addressed?
13.3
Have data protection requirements been described?
10.1
Comments:
This protocol has not yet undergone any ethical review procedure.
Section 14: Amendments and deviations
Yes
No
N/A
Section 
Number
14.1
Does the protocol include a section to document 
amendments and deviations? 
5.0
Comments:
Section 15: Plans for communication of study results
Yes
No
N/A
Section 
Number
15.1
Are plans described for communicating study results 
(e.g. to regulatory authorities)? 
12.0

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15.2
Are plans described for disseminating study results 
externally, including publication?
12.0
Comments:
This is a Master protocol

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ANNEX 3. REQUIREMENTS FOR THE LOCALIZED PROTOCOLS
MULTI-COUNTRY STUDY: 
Section of the master protocol
COUNTRY-SPECIFIC STUDIES: 
To be specified in localized protocols
Required specifications
Optional additional 
specifications; the obtained 
results of these country-
specific additions will not be 
included in the combined 
results of the multi-country
study
6 MILESTONES
Timelines for the country-
specific studies
-
8 RESEARCH QUESTION AND 
OBJECTIVES
Specification of which 
objectives can be addressed
Additional objectives
9.2 SETTING
Marketing authorization dates 
for study drugs (if new country
for which the date is not 
included in the master 
protocol)
Study period and follow-up, 
depending on the dates of the 
marketing authorizations of the 
study drugs and data 
availability in each country’s 
data sources
-
9.2.2 Study population
Used definition for T2DM
-
9.3 VARIABLES
Adaptation of all master 
variables i.e. locally used 
definitions for all variables, 
including coding systems or 
other definitions (for all 
variables under section 9.3)
Availability of the variables 
listed in the master protocol
(for all variables under section 
9.3)
Definitions for additional 
variables, beyond the variables 
listed in the master protocol
9.3.1 Exposures: study drugs
Definition of a daily dose for 
the study drugs
Exposure period
Additional SGLT-2 inhibitors, 
DPP-4 inhibitors or other drugs 
included in country-specific
studies. 
Alternative comparator drugs
Additional definitions for
considering concomitant use of a 
SGLT-2 inhibitor and a DPP-4 
inhibitor, of dose effects
9.3.2 Outcomes
-
Further outcomes
9.3.3 Covariates at baseline (baseline 
characteristics)
-
Additional covariates, to be used 
in additional analyses
9.3.4 Other variables required for 
analyses
-
Additional variables, to be used 
in additional analyses (e.g. for 
stratification)

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MULTI-COUNTRY STUDY: 
Section of the master protocol
COUNTRY-SPECIFIC STUDIES: 
To be specified in localized protocols
Required specifications
Optional additional 
specifications; the obtained 
results of these country-
specific additions will not be 
included in the combined 
results of the multi-country
study
9.4 DATA SOURCES
Utilized data sources, 
including whether dispensation 
data or other records of the 
drug use are utilized and 
whether primary care is 
included
-
9.6 DATA MANAGEMENT
Detailed data management 
procedures including the used 
statistical software
-
9.7 DATA ANALYSIS
-
Any additional analyses, 
including e.g. additional models 
with additional adjusting 
variables, models considering 
time-dependent confounding or 
analyses considering dose 
effects
9.8 QUALITY CONTROL
Description of quality control 
procedures for the localized 
protocols, localized SAPs, 
country-specific analyses, and 
country-specific study reports
-
9.9 LIMITATIONS OF THE 
RESEARCH METHODS
9.12 BIAS
Any country-specific
limitations or sources of bias
10 PROTECTION OF HUMAN 
SUBJECTS
Details on the protection of 
human subjects, including 
applicable applications for 
ethical approval and data 
protection according to 
national legislation
DPP-4=dipeptidyl peptidase-4; ICD-10=International Classification of Diseases, 10th revision; SAP=statistical analysis plan;
SGLT-2=sodium-glucose cotransporter-2; T1DM=type 1 diabetes mellitus; T2DM=type 2 diabetes mellitus.

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ANNEX 4. ALTERNATIVE DEFINITION OF EXPOSURE PERIODS
(DRUG SUPPLY UNAVAILABLE)
If there is no sufficient data available to define drug supplies (such as data on prescriptions or 
dispensations) in the local data source, exposure periods of study drugs can be defined based 
on other available records of drug use, such as manual records. Drug exposure will be 
assumed to begin on the date of a record of drug use, or at on the first treatment day if 
specified.
If defining drug supplies is not feasible from the available data sources, only the grace period 
can be used in the definition of drug exposure. This definition of grace period should reflect 
local treatment practices, i.e. which gap is allowed between two consecutive records of drug 
use in continuous exposure to the drug. In ANNEX 4 Figure 1 below, a grace period of 90 
days is used as an example. If a new record is not observed during the grace period, the 
exposure will end at the end of that grace period.
If a subsequent supply occurs before the previous supply has finished, the start of the 
subsequent supply might be shifted considering local treatment practices.
ANNEX 4 Figure. 1: Illustration of combining exposure periods with grace periods and the 
differences between the AT and ITT approaches.
AT=as-treated; ITT=intention to treat

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ANNEX 5. DEFINITIONS FOR INCLUSION AND EXCLUSION CRITERIA 
ICD-9
ICD-10
ATC
Comments
Inclusion criteria
Dispensation or any other record
of empagliflozin, any SGLT-2 
inhibitor, or any DPP-4 inhibitor 
use during the study period 
-
-
Empagliflozin (including fixed-
dose combinations with other 
drugs than DPP-4 inhibitors):
A10BK03
A10BD20
Any SGLT-2 inhibitor 
(including fixed-dose 
combinations with a SGLT-2 
inhibitor and another drug than 
DPP-4 inhibitor):
A10BK01
A10BD15
A10BK03
A10BD20
A10BK02
A10BD16
A10BK04
A10BD23
Any DPP-4 inhibitor (including 
fixed-dose combinations with a 
DPP-4 inhibitor and another 
drug than SGLT-2 inhibitor):
A10BH01
A10BD07
A10BD12
A10BH51
Includes both free and fixed-
dose combination, also at index 
date
No dispensation or any other 
record of any other SGLT-2 
inhibitor or DPP-4 inhibitor use
during the preceding 12 months 
including at index date

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ICD-9
ICD-10
ATC
Comments
A10BH02
A10BD08
A10BH03
A10BD10
A10BH04
A10BD09
A10BD13
A10BH05
A10BD11
Having a diagnosis of T2DM 
before the index date, based on 
ICD-10 codes or other available 
data
250.x0, 250.x2
E11
≥1 filled dispensation/any other 
record of metformin use at any 
time in the past:
A10BA02 metformin
A10BD15 Dapagliflozin and 
metformin
A10BD20 Empagliflozin and 
metformin 
A10BD16 Canagliflozin and 
metformin 
A10BD23 Ertugliflozin and 
metformin
A10BD07 Sitagliptin and 
metformin
A10BD08 Vildagliptin and 
metformin 
A10BD10 Saxagliptin and 
metformin
A10BD13 metformin and 
alogliptin2
A10BD11 Linagliptin and 
Most appropriate time-window 
prior to the index date will be 
detailed in the localized 
protocols according to 
validated or standard 
definitions used in the country 
and data source.

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ICD-9
ICD-10
ATC
Comments
metformin 
A10BD05 metformin and 
pioglitazone
A10BD03 metformin and 
rosiglitazone
Exclusion criteria
Aged <18 years on the first 
dispensation date or date of the 
first record of empagliflozin, any 
SGLT-2 inhibitor or any DPP-4 
inhibitor use
-
-
-
Type 1 diabetes mellitus
250.x1 or 250.x3
E10
-
Secondary diabetes
249.xx
E08, E09, E13 
-
Diabetes mellitus due to 
underlying condition, drug or 
chemical induced diabetes 
mellitus, or other specified 
diabetes mellitus
Gestational diabetes
648.8x
O24.4, O24.1 
-
Gestational diabetes mellitus or 
pre-existing type 2 diabetes 
mellitus, in pregnancy, 
childbirth, and the puerperium
Having a diagnosis of ESRD 
during the 12 months before the 
index date
At least 2 measurements 
separated by at least 30 
days (but no more than 
12 months)
≥2 of the following 
diagnosis or procedure 
codes (either inpatient or 
At least 2 
measurements 
separated by at least 
30 days (but no more 
than 12 months) 
Defined as 2 codes 
(either inpatient or 
Erythropoietin B03XA01
Calcium acetate V03AE07
Calcium acetate+Magnesium 
carbonate V03AE04
Lanthanum carbonate V03AE03
Sevelamer V03AE02
Sucroferric oxyhydroxide 
Having any of the following:
eGFR <15,
diagnoses or procedure related 
to ESRD, or
diagnoses or procedures related 
to kidney transplant

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ICD-9
ICD-10
ATC
Comments
outpatient), separated by 
at least 30 days
Diagnoses:
585.5x, 585.6x, V56.0x, 
V56.8x, V45.1x
Procedures:
39.95, 54.98
Kidney transplant, 
defined as ≥1 of the 
following diagnosis or 
procedure codes 
(inpatient or outpatient):
Diagnoses: 
V42.0x, 996.81
Procedures: 
55.6x
outpatient), separated 
by at least 30 days 
Codes include:
Renal dialysis:
Z99.2
Procedures related to 
renal dialysis: 
5A1D00Z, 5A1D60Z, 
3E1M39Z
Chronic kidney 
disease, Stage V (for 
ESRD with no 
mention of dialysis): 
N18.5
End-stage renal 
disease (for ESRD 
with dialysis):
N18.6
Encounter for 
dialysis: Z49.31, 
Z49.32
Defined as either 1 
inpatient or 1 
outpatient code
Codes include:
Kidney transplant 
status:
V03AE05
Ferric citrate V03AE08
Except for patients with a 
diagnosis of primary 
hyperparathyroidism (ICD-10: 
E21.0) 

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ICD-9
ICD-10
ATC
Comments
Z4822, Z940, 
OTS00ZZ, OTS10ZZ, 
OTY00Z x, OTY10Zx
Complications of 
transplanted kidney:
Z4822, 0TY00Z0, 
0TY00Z1, 0TY00Z2, 
0TY10Z0, 0TY10Z1, 
0TY10Z2
Transplant of the 
kidney:
0TY00Zx, 0TY10Zx,
Z940 (Exclude 
0TS00ZZ, OTS10ZZ) 
<12 months of available data 
before the index date, and/or no 
complete history of drug 
dispensations/other records of the 
drug use during this period
-
-
-
For example, known gaps in 
the drug data, or known 
inadequate validity of the drug 
data 
Missing or ambiguous data on 
age or sex
-
-
-
As available in the data source
DPP-4=dipeptidyl peptidase-4; eGFR=estimated glomerular filtration rate; ESRD=end-stage renal disease; ICD-9=International Classification of Diseases, 9th revision; ICD-
10=International Classification of Diseases, 10th revision; SGLT-2=sodium-glucose cotransporter-2; T2DM=type 2 diabetes mellitus.

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ANNEX 6. VARIABLE DEFINITIONS FOR OUTCOMES
Outcome
ICD-9
ICD-10
Comments
Primary effectiveness outcomes
Hospitalization for heart failure*
428.x, 398.91, 402.01, 
402.11, 402.91, 404.01, 
404.11, 404.91, 404.03, 
404.13, 404.93
I09.81, I11.0, I13.0, I13.2, I50.1x, I50.2x, I50.3x, 
I50.4x, 150.9
Any diagnosis of heart failure 
associated with healthcare 
encounters, including 
hospitalizations and specialist 
outpatient and primary care 
encounters, or dispensation or any 
other record of the high-ceiling
diuretics (loop diuretics)
428.x, 398.91, 402.01, 
402.11, 402.91, 404.01, 
404.11, 404.91, 404.03, 
404.13, 404.93
I09.81, I11.0, I13.0, I13.2, I50.1x, I50.2x, I50.3x, 
I50.4x, 150.9
ATC for high -ceiling diuretics 
(loop diuretics):
C03C
Myocardial infarction
410.X, excluding 410.x2
I21.0x, I21.1x, I21.2x, I21.3x, I21.4x, I22.0x, 
I22.0x, I22.1x, I22.2x, I22.8x, I22.9x, I25.2x
Stroke
430.xx, 431.xx, 433.x1, 
434.xx (excluding 
434.x0), 436.x
Subarachnoid hemorrhage (SAH):
I60xx
Intracerebral hemorrhage (ICH):
I610, I611, I612, I613, I614, I615, I616, I618, I619
Occlusion and stenosis of precerebral arteries 
with cerebral infarction:
I6300, I63011, I63012, I63013, I63019, I6302, 
I63031, I63032, I63033, I63039, I6309, I6310, 
I63111, I63112, I63113, I63119, I6312, I63131, 
I63132, I63133, I63139, I6319, I6320, I63211, 

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Outcome
ICD-9
ICD-10
Comments
I63212, I63213, I63219, I6322, I63231, I63232, 
I63233, I63239, I6329, I6330, I6331x, I6332x, 
I6333x, I6334x, I6339, I6340, I6341x, I6342x, 
I6343x, I6344x, I6349, I6350, I6351x, I6352x, 
I6353x, I6354x, I6359, I636, I638, I639, I6789
Acute, but ill-defined cerebrovascular events:
I6789
All-cause mortality
Any code
Any code
Secondary cardiovascular effectiveness outcomes
CV mortality 
390-459
I00 to I99 
Coronary revascularization 
procedure
a)
PTCA, inpatient 
procedure: 00.66, 
36.01, 36.02, 36.03, 
36.05, 36.09
b)
(no ICD-9)
c)
Stenting, inpatient 
procedure: 36.06, 
36.07
d)
CABG, inpatient 
procedure: 36.1x, 
36.2x
e)
(no ICD-9)
a)
PTCA
(no ICD-10 available)
b)
coronary bypass:
02.10083, 02.1008x, 02.1009x, 02.100Ax, 
02.100Jx, 02.100Kx, 02.100Zx, 02.10483, 
02.10488, 02.10489, 02.1048x, 02.1049x, 
02.1049x, 02.104Ax, 02.104Jx, 02.104Kx, 
02.104Zx, 02.1108x, 02.1109x, 02.110Ax, 
02.110Jx, 02.110Kx, 02.110Zx, 02.1148x, 
02.1149x, 02.114Ax, 02.114Jx, 02.114Kx, 
02.114Zx, 02.1208x, 02.1209x, 02.120Ax, 
02.120Jx, 02.120Kx, 02.120Zx, 02.1248x, 
02.1249x, 02.124Ax, 02.124Jx, 02.124Kx, 
02.124Zx, 02.1308x, 02.1309x, 02.130Ax, 
02.130Jx, 02.130Kx, 02.130Zx, 02.1348x, 
02.1349x, 02.134Ax, 02.134x, 02.134Kx, 
02.134Zx, 02.1K0Zx, 02.1K4Zx, 02.1L08X, 
02.1L09x, 02.IL0Ax, 02.1L0Jx, 02.IL0Kx, 
02.1l0Zx, 02.1L0Zx, 02.1L48X, 02.1L49x, 
Having diagnoses or procedures 
related to 
a)
PTCA, 
b)
coronary bypass, 
c)
stenting, 
d)
CABG, or 
e)
transmyocardial 
revascularization

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Outcome
ICD-9
ICD-10
Comments
02.1L4xx, 02.7004x, 02.7006x, 02.7007x, 
02.700Dx, 02.700Ex, 02.700Fx, 02.700Gx, 
02.700Tx, 02.700Zx, 02.703xx, 02.704xx, 
02.7104x, 02.7105x, 02.7106x, 02.7107x, 
02.710Dx, 02.710Ex, 02.710Fx, 02.710Gx, 
02.710Tx, 02.710Zx, 02.7134x, 02.7135x, 
02.7136x, 02.7137x, 02.713Dx, 02.713Ex, 
02.713Fx, 02.713Gx, 02.713Tx, 02.713Zx, 
02.7144x, 02.7145x, 02.7146x, 02.7147x, 
02.714Dx, 02.714Ex, 02.714Fx, 02.714Gx, 
02.714Tx, 02.714Zx, 02.7204x, 02.72056, 
02.72066, 02.7206Z, 02.72076, 02.7207Z, 
02.720Dx, 02.720Ex, 02.720Fx, 02.720Tx, 
02.720Zx, 02.7234x, 02.7235x, 02.7236x, 
02.7237x, 02.7237x, 02.723Dx, 02.723Ex, 
02.723Fx, 02.723Gx, 02.723Tx, 02.723Tx, 
02.723Zx, 02.723Zx, 02.7244x, 02.7245x,
02.7246x, 02.7247x, 02.724Dx, 02.724Ex, 
02.724Fx, 02.724Gx, 02.724Tx, 02.7304x, 
02.7304x, 02.7305x, 02.7306x, 02.7307x, 
02.730Dx, 02.730Ex, 02.730Fx, 02.730Gx, 
02.730Tx, 02.730Zx, 02.7334x, 02.7335x, 
02.7336x, 02.7337x, 02.733Dx, 02.733Ex, 
02.733Fx, 02.733Gx, 02.733Tx, 02.733Zx, 
02.7344x, 02.7345x, 02.7346x, 02.7347x, 
02.734Dx, 02.734Ex, 02.734Fx, 02.734Gx, 
02.734Tx, 02.734Zx, 02.C00Zx, 02.C03Zx, 
02.C04Zx, 02.C10Zx, 02.C13Zx, 02.C14Zx, 
02.C20Zx, 02.C23Zx, 02.C24Zx, 02.C30Zx, 
02.C33Zx, 02.C34Zx

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Outcome
ICD-9
ICD-10
Comments
c)
Stenting:
02ю7004чб 02ю7005чб 02ю7006чб 02ю7007чб
02ю700Вчб 02ю700Учб 02ю700Ачб
02ю700Пчб 02ю700Ечб 02ю700Ячб 02ю7034чб
02ю7035чб 02ю7036чб 02ю7037чб 02ю703Вчб
02ю703Учб 02ю703Ачб 02ю703Пчб
02ю703Ечб 02ю703Ячб 02ю7044чб 02ю7045чб
02ю7046чб 02ю7047чб 02ю704Вчб 02ю704Учб
02ю704Ачб 02ю704Пчб 02ю704Ечб 02ю704Ячб
02ю7104чб 02ю7105чб 02ю7106чб 02ю7107чб
02ю710Вчб 02ю710Учб 02ю710Ачб
02ю710Пчб 02ю710Ечб 02ю710Ячб 02ю71346б
02ю7134Яб 02ю71356б 02ю7135Яб 02ю71366б
02ю7136Яб 02ю71376б 02ю7137Яб 02ю713В6б
02ю713ВЯб 02ю713У6б 02ю713УЯб
02ю713А6б 02ю713АЯб 02ю713П6б
02ю713ПЯб 02ю713Е6б 02ю713ЕЯб
02ю713Я6б 02ю713ЯЯб 02ю71446б 02ю7144Яб
02ю71456б 02ю7145Яб 02ю71466б 02ю7146Яб
02ю71476б 02ю7147Яб 02ю714В6б 02ю714ВЯб
02ю714У6б 02ю714УЯб 02ю714А6б
02ю714АЯб 02ю714П6б 02ю714ПЯб
02ю714Е6б 02ю714ЕЯб 02ю714ЯЯб 02ю72046б
02ю7204Яб 02ю72056б 02ю7205Яб 02ю72066б
02ю7206Яб 02ю72076б 02ю7207Яб 02ю720В6б
02ю720ВЯб 02ю720У6б 02ю720УЯб
02ю720А6б 02ю720АЯб 02ю720П6б
02ю720ПЯб 02ю720Е6б 02ю720ЕЯб
02ю720Я6б 02ю720ЯЯб 02ю72346б 02ю7234Яб
02ю72356б 02ю7235Яб 02ю72366б 02ю7236Яб

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Outcome
ICD-9
ICD-10
Comments
02ю72376б 02ю7237Яб 02ю723В6б 02ю723ВЯб
02ю723У6б 02ю723УЯб 02ю723А6б
02ю723АЯб 02ю723П6б 02ю723ПЯб
02ю723Е6б 02ю723ЕЯб 02ю723Я6б
02ю723ЯЯб 02ю72446б 02ю7244Яб 02ю72456б
02ю7245Яб 02ю72466б 02ю7246Яб 02ю72476б
02ю7247Яб 02ю724В6б 02ю724ВЯб
02ю724У6б 02ю724УЯб 02ю724А6б
02ю724АЯб 02ю724П6б 02ю724Е6б
02ю724ЕЯб 02ю724Я6б 02ю724ЯЯб
02ю73046б 02ю7304Яб 02ю73056б 02ю7305Яб
02ю73066б 02ю7306Яб 02ю73076б 02ю7307Яб
02ю730В6б 02ю730ВЯб 02ю730У6б
02ю730УЯб 02ю730А6б 02ю730АЯб
02ю730П6б 02ю730ПЯб 02ю730Е6б
02ю730ЕЯб 02ю730ЕЯб 02ю730Я6б
02ю730ЯЯб 02ю73346б 02ю7334Яб 02ю73356б
02ю7335Яб 02ю73366б 02ю7336Яб 02ю73376б
02ю73376б 02ю7337Яб 02ю733В6б 02ю733ВЯб
02ю733У6б 02ю733УЯб 02ю733А6б
02ю733АЯб 02ю733П6б 02ю733ПЯб
02ю733Е6б 02ю733ЕЯб 02ю733Я6б
02ю733ЯЯб 02ю733ЯЯб 02ю73446б
02ю7344Яб 02ю73456б 02ю7345Яб 02ю73466б
02ю73476б 02ю7347Яб 02ю34В6б 02ю734ВЯб
02ю734У6б 02ю734УЯб 02ю734А6б
02ю734АЯб 02ю734П6б 02ю734ПЯб
02ю734Е6б 02ю734ЕЯб 02ю734Я6б
02ю734ЯЯб 02юС00Я6б 02юС03Я6б
02юС03ЯЯб 02юС04Я6б 02юС10Я6б

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Outcome
ICD-9
ICD-10
Comments
02юС13Я6б 02юС13ЯЯб 02юС14Я6б
02юС20Я6б 02юС23Я6б 02юС23ЯЯб
02юС24Я6б 02юС30Я6б 02юС33ЯЯб
02юС34Я6б
d)
CABG
(No code available)
e)
Transmyocardial revascularization:
021K0Z5, 021K4Z5, 021L0Z5, 021L4Z5, 
02QA3ZZ, 02QA4ZZ, 02QB3ZZ, 02QB4ZZ, 
02QC3ZZ, 02QC4ZZ
Secondary renal effectiveness outcomes
End-stage renal disease
a)
ESRD, defined as 
having ≥2 of the 
following diagnosis 
or procedure codes 
(either inpatient or 
outpatient), 
separated by at least 
30 days
Diagnoses: 585.5x, 
585.6x, V56.0x, 
V56.8x, V45.1x
Procedures: 39.95, 
54.98
b)
Kidney transplant, 
defined as ≥1 of the 
following diagnosis 
or procedure codes 
a)
ESRD,
defined as 2 codes (either inpatient or 
outpatient), separated by at least 30 days 
Codes include:
Renal dialysis:
Z99.2
Procedures related to renal dialysis: 5A1D00Z, 
5A1D60Z, 3E1M39Z
Chronic kidney disease, Stage V (for ESRD 
with no mention of dialysis): N18.5
End-stage renal disease (for ESRD with 
dialysis): 
N18.6
Encounter for dialysis: 
Z49.31, Z49.32
Having any of the following
a)
diagnoses or procedure related 
to ESRD, or
b)
diagnoses or procedures related 
to kidney transplant

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Outcome
ICD-9
ICD-10
Comments
(inpatient or 
outpatient):
Diagnoses: V42.0x, 
996.81
Procedures: 55.6x.
Kidney transplant, defined as either 1 inpatient 
or 1 outpatient code
Codes include:
Kidney transplant status:
Z4822, Z940, OTS00ZZ, OTS10ZZ, OTY00Z x,
OTY10Zx
Complications of transplanted kidney:
Z4822, 0TY00Z0, 0TY00Z1, 0TY00Z2, 
0TY10Z0, 0TY10Z1, 0TY10Z2
Transplant of the kidney: 
0TY00Zx, 0TY10Zx, Z940 (Exclude 0TS00ZZ, 
OTS10ZZ)
Decline from normal kidney 
function (≥60ml/min/1,73m2) to 
abnormal kidney function 
(<60ml/min/1,73m2). 
Categorized according to the 
following serum creatinine values 
(ml/min/1,73m2)
Normal kidney function: ≥60
Abnormal kidney function:
<60<15
Progression from normoalbuminuria
to micro- or macroalbuminuria 
Categorized according to the 
following albuminuria levels 
(mg/g)
Normoalbuminuria: <30
Micro- or macroalbuminuria: 
≥30>30
Secondary safety outcomes
Bone fracture
Hip fracture diagnosis:
Osteoporosis with pathological fracture:

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Outcome
ICD-9
ICD-10
Comments
ICD-9 diagnosis 
(820.xx, 733.14, 733.96) 
during hospitalization 
AND procedure code 
(ICD-9: 78.55, 79.05, 
79.15, 79.25, 79.35, 
79.65) during 
hospitalization 
Pelvis fracture 
diagnosis:
808.xx, 733.98
Radius/ulna fracture 
diagnosis:
(ICD-9: 813.xx, 733.12) 
AND procedure (ICD-9: 
78.53, 79.02, 79.12, 
79.22, 79.32, 79.62) 
within 30 days of 
fracture date 
Humerus fracture 
diagnosis:
(ICD-9: 812.xx, 733.11) 
AND procedure (ICD-9: 
78.52, 79.01, 79.11, 
79.21, 79.31, 79.61) 
within 30 days of 
fracture date 
M80.021, M80.022, M80.029, M80.031, M80.032, 
M80.039, M80.051, M80.052, M80.059, M80.821, 
M80.822, M80.829, M80.831, M80.832, M80.839, 
M80.851, M80.852, M80.859, 
Disorders of continuity of bone:
M84.350, M84.359, M84.421, M84.422, M84.429, 
M84.431, M84.432, M84.433, M84.52x, M84.53x, 
M84.55x, M84.62x, M84.63x, M84.65x, M84.75x, 
Fracture of lumbar spine and pelvis:
S32.30x, S32.31x, S32.39x, S32.40x, S32.41x, 
S32.42x, S32.43x, S32.44x, S32.45x, S32.46x, 
S32.47x, S32.48x, S32.49x, S32.50x, S32.51x, 
S32.59x, S32.60x, S32.61x, S32.69x, S32.81x, 
S32.82x, S32.89x, S32.9x
Femur fracture:
S72.01x, S72.02x, S72.03x, S72.04x, S72.05x, 
S72.06x, S72.09x, S72.11x, S72.12x, S72.13x, 
S72.14x, S72.21x, S72.22x, S72.23x, S72.24x, 
S72.25x, S72.26x, S79.00x, S79.01x, S79.09x
Radius/ulna fracture diagnosis: S52.01x, 
S52.02x, S52.03x, S52.04x, S52.09x, S52.10x, 
S52.11x, S52.12x, S52.13x, S52.18x, S52.2x, 
S52.3x, S52.5x, S52.61x, S52.62x, S52.69x, 
S52.90x, S52.91x, S52.92x, S59.00x, S59.01x, 
S59.02x, S59.03x, S59.04x, S59.09x, S59.10x 
S59.11x, S59.12x, S59.13x, S59.14x, S59.19x, 
S59.20x, S59.21x, S59.22x, S59.23x, S59.24x, 
S59.29x

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Outcome
ICD-9
ICD-10
Comments
Humerus fracture diagnosis:
S42.20x, S42.21x, S42.22x, S42.23x, S42.24x, 
S42.25x, S42.26x, S42.27x, S42.29x, S42.3x, 
S42.4x, S49.01x, S49.02x, S49.03x, S49.04x, 
S49.09x, S49.11x, S49.12x, S49.13x, S49.14x, 
S49.19x
Femur fracture:
S72.01x, S72.02x, S72.03x, S72.04x, S72.05x, 
S72.06x, S72.09x, S72.11x, S72.12x, S72.13x, 
S72.14x, S72.21x, S72.22x, S72.23x, S72.24x, 
S72.25x, S72.26x, S79.00x, S79.01x, S79.09x
Diabetic ketoacidosis
Inpatient diagnosis: 
250.1x
E08.1, E09.1, E10.1, E13.1
Severe hypoglycemia
Any-position ED or 
primary inpatient ICD-
9 diagnosis:
251.0, 251.1x, 251.2x, or 
250.8x. 
Outcomes identified by 
250.8x are not included 
if they co-occur with 
one of the following 
diagnoses:
259.8, 272.7, 681.xx, 
682.xx, 686.9, 707.1x, 
707.2x, 707.8, 707.9, 
709.3, 730.0x, 730.1x, 
730.2x, 731.8. 
E160, E161, E162

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Outcome
ICD-9
ICD-10
Comments
Lower-limb amputation
84.10-84.18
(not available) 
Acute kidney injury that
requires dialysis
Inpatient ICD-9 
diagnosis:
584.5x ARF with a 
lesion of tubular necrosis
584.6x ARF with a 
lesion of renal cortical 
necrosis
584.7x ARF with lesion 
of renal medullary 
[papillary] necrosis
584.8x ARF with 
another specified 
pathological lesion in the 
kidney
584.9x ARF, unspecified
AND any of the 
following inpatient 
codes (within the same 
claim):
39.95 hemodialysis
V45.1 renal dialysis 
status
V56.0 extracorporeal 
dialysis
V56.1 fitting and 
adjustment of a dialysis 
catheter
N17
Secondary outcomes on healthcare resource utilization and cost of care

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Outcome
ICD-9
ICD-10
Comments
Healthcare resource utilization
Outpatient healthcare visits

Primary care visits, specialist 
outpatient care visits or office 
visits, excluding emergency 
care, according to data 
availability

Emergency department visits 
Inpatient healthcare visits

Hospital admissions 

Inpatient days 

Length of stay 
Drug use in outpatient and inpatient 
care

Dispensations/other records 
of the drug use
Cost of care
Costs associated with healthcare 
resource utilization outcomes
ARF=acute renal failure; CABG=coronary artery bypass grafting; CV=cardiovascular; eGFR=estimated glomerular filtration rate; ED=emergency department; ESRD=end-stage 
renal disease; ICD-9=International Classification of Diseases, 9th revision; ICD-10=International Classification of Diseases, 10th revision; PTCA=percutaneous transluminal 
coronary angioplasty.

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ANNEX 7. DEFINITIONS FOR COVARIATES AT BASELINE
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
Sociodemographic characteristics (closest to index date)
Age 
By year
-
-
-
By category (18-54, 55-64, 65-74, 75+)
-
-
-
Sex 
female, male
-
-
-
Race 
Categorization as applicable in the country
-
-
-
Socioeconomic status 
By category (low, intermediate, high). Can 
include e.g. educational level or income 
level, as deemed appropriate by the 
countries
-
-
-
Calendar time by 
3-month block
By 3-month block
-
-
-
By day within the 3-month block
-
-
-
Covariates related to lifestyle (closest to index date)
Obesity 
Having:
a) recorded diagnoses/procedures related 
to obesity, or 
b) filled dispensations/other records of the 
drug use related to obesity care
Diagnoses: E66, excluding E66.3
A08A anti-obesity 
preparations, excl. diet 
products
Overweight 
-
278.02, V85.2x
E66.3
-
Smoking 
-
V15.82, 305.1x, 
649.0x, 989.84
F17, Z72.0, T65.2
-

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Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
Alcohol abuse or 
dependence
-
291.xx, 303.xx, 
305.0x, 571.0x, 
571.1x, 571.2x, 
571.3x, 357.5x, 
425.5x, E860.0x, 
V11.3x
F10, K70, G62.1, I42.6, Z71.4
-
Drug abuse or 
dependence 
-
292.xx, 304.xx, 
305.2x-305.9x, 
648.3x
F11; F12, F13, F14, F15, F16, F18, 
F19, Z71.5
-
Diabetes complications (12 months preceding index date) *
Diabetic retinopathy 
-
362.0x
E103.1x, E103.2x, E103.3x, 
E103.4x, E103.5x, E113.1x, 
E113.2x, E113.3x, E113.4x, 
E113.5x
-
Diabetes with other 
ophthalmic 
manifestations
Diagnoses related to 
Diabetes with ophthalmic manifestation
(without mention of other retinal 
disorders), 
Diabetic cataract, 
Diabetic glaucoma
250.5x (without 
362.01-362.07), 
366.41 (diabetic 
cataract), 365.44 
(diabetic 
glaucoma)
H28, H42, E08.36, E08.39, E09.36, 
E09.39, E10.36, E10.39, E11.36, 
E11.39, E13.36, E13.39
-
Retinal detachment, 
vitreous hemorrhage, 
vitrectomy
Related diagnoses or procedures
Diagnoses: 
361.9x, 379.23
Procedure: 14.7x
E103.5x, E113.1x, E113.2x, 
E113.3x, E113.4x, E113.5x
-
Retinal laser 
coagulation therapy
-
14.24, 14.34, 
14.54 
08.5x, 08.Qx 
-

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Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
Diabetic neuropathy 
-
250.6x, 357.2x, 
337.1
G99.0, G59.0, G63.2, E08.4, E09.4, 
E10.4, E11.4, E13.4
-
Diabetic nephropathy 
-
250.4x, 583.81
E092.1x, E092.2x, E092.9x, 
E102.2x, E102.9x, E106.5x, 
E112.1x, E112.2x, E112.9x, 
E132.2x, E132.9x, 
-
Hypoglycemia 
Diagnoses related to
Hypoglycemia, or
Hypoglycemic events
Diagnoses: 
251.1x, 251.20, 
962.30
Also, 250.8x as 
long as none of 
the following 
codes are co-
occurring 
diagnoses (i.e. 
same day): 259.8, 
272.7, 681.xx, 
682.xx, 686.9x, 
707.xx, 709.3, 
730.0-730.2, 
731.8
E13649, E1369, E160, E161, E162
-
Hyperglycemia
-
790.29
R73.0x, R73.9
-
Disorders of fluid 
electrolyte and acid-
base balance
-
276.xx
E870, E871, E872, E873, E874, 
E869, E860, E877.1, E877.0, 
E877.9, E875, E876, E878
-
Diabetic ketoacidosis
250.1x
E1010, E1310
-

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Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
Hyperosmolar 
hyperglycemic 
nonketotic syndrome
-
250.2x
E110.0, E110.1, E130.0, E130.1
-
Diabetes with 
peripheral circulatory 
disorders 
-
250.7x, 443.81
E105.x, E.115.x, E.116.x, E.135.x
-
Diabetic foot 
-
707.1x
L97.90x, L97.91x, L97.92x, 
I70.23x, I70.24x, I70.33x, I70.34x, 
I70.43x, I70.44x, I70.53x, I70.54x, 
I70.63x, I70.64x, I70.73x, I70.74x, 
L97.10x, L97.11x, L97.12x, 
L97.20x, L97.21x, L97.22x, 
L97.30x, L97.31x, L97.32x, 
L97.40x, L97.41x, L97.42x, 
L97.50x, L97.51x, L97.52x, 
L97.80x, L97.81x, L97.82x, 
E116.21, E136.21, E106.21
-
Gangrene 
-
785.4x
I70.2x, I70.3x, I70.4x, I70.5x, 
I70.6x, I70.7x, 
E105.2x, E115.2x, E135.2x
-
Lower extremity 
amputation 
Diagnoses or procedures related to lower 
limb amputation
Diagnoses: 
V49.7x 
(excluding 
V49.76 or 
V49.77)
Procedures: 
84.10-84.17
Z89
-

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Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
Osteomyelitis 
-
730.xx
M860xx, M860x,
-
Skin infections 
-
680.xx-686.xx
L02.0x, L02.1x, L02.2x, L02.4x, 
L02.5x, L02.6x, L02.7x, L02.8x, 
L02.9x, L03.0x, K12.2, L03.1x, 
L03.2x, L03.3x, L03.8, L03.9, 
L98.3, L04.0, L04.1, L04.2, L04.3, 
L04.8, L04.9, L01.0x, L01.1, 
L05.0x, L05.9x, L08.0, L88, 
L08.8x, L92.8, L98, B78.1, E832, 
L08.82, L08.89, L08.9
-
Erectile dysfunction
-
607.84
N52.0x, N52.1x, N52.3x, N52.8x, 
N52.9x
-
Diabetes with 
unspecified 
complication
-
250.9x
E118, E138, E108
-
Diabetes mellitus 
without mention of 
complications 
-
250.0x
E109, E119, E139
-
Other comorbidities (12 months preceding index date)
Hypertension 
1 inpatient or 2 outpatient encounters with 
any diagnosis codes for hypertension
401.x – 405.x
I10, I16.0, I16.1, I11.9, I11.0, I12.9, 
I12.0, I13.10, I13.0, I13.11, I13.2, 
I15.0, I15.8, I15.1, N26.2, I15.2, 
I15.9
-
Hyperlipidemia 
-
272.0x-272.4x
E780.x, E782x E784, E785
-
Ischemic heart disease 
-
410.xx-414.xx
I20.0, I20.1x, I20.8x, I20.9x, 
I21.01, I21.02, I21.09, I21.19, 
I21.2x, I21.3x, I21.4x, I22.0, 
-

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Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
I22.1x, I22.2x, I22.8x, I22.9x, 
I24.0x, I24.1, I24.8x, I24.9x, 
I25.1x, I25.2x, I25.3x, I25.6x, 
I25.7x, I25.8x, I25.9x
Acute MI 
-
410.xx
I21.9x, I21.1x, I21.2x, I21.4x, 
I21.3x, I22.8x,
-
Acute coronary 
syndrome or unstable 
angina 
-
411.xx
I20.0x, I24.0x, I24.1x, I24.8x, 
I24.9x, I25.1x, I25.7x
-
Old MI 
-
412.xx
I25.2
-
Stable angina 
-
413.xx
I20.1, I20.8, I20.9, I2.1x, I25.7x
-
Coronary 
atherosclerosis and
other forms of chronic 
ischemic heart disease
-
414.xx
I25.1x, I25.7x, I25.8x, I25.3x, 
I25.5x, I25.6x, I25.9x
-
Other atherosclerosis 
Diagnoses related to
Arteriosclerotic cardiovascular disease, or 
Generalized and unspecified 
atherosclerosis
429.2x 
440.9x 
I25.1x,
I70.90, I70.91
-
Previous cardiac 
procedure 
Diagnoses or procedures related to 
CABG,
PTCA,
Stent, or
Transmyocardial revascularization
00.66, 36.01, 
36.02, 36.03, 
36.04, 36.05, 
36.06, 36.07, 
36.09, 36.1x, 
36.2x
(No ICD-10 available)
(No ICD-10 available)
(No ICD-10 available)
Z95.5, Z98.61, Z95.1 
-

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Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
History of CABG or 
PTCA
V45.81, V45.82
Any stroke 
-
430.xx, 431.xx, 
433.xx, 434.xx, 
436.xx
I63.5x, I63.6x, I63.8x, I63.9x, 
I65.0x, I65.1x, I65.2x, I66.0x, 
I66.1x, I66.2x, I66.3x, I66.8x, 
I66.9x
-
Ischemic stroke (with 
and without mention 
of cerebral infarction)
-
433.xx, 434.xx, 
436.xx
I63.xx I65.xx I66.xx
-
Hemorrhagic stroke 
-
430.xx, 431.xx
I60.xx, I61.xx,
-
Transient cerebral 
ischemia and related 
syndromes
-
435.xx
G45.x
-
Other cerebrovascular 
disease
-
432.xx, 437.xx
I00.xx, I0x.x, I3x.xx, I40.xx, 
I41.xx, I42.xx, I43.xx, I71.xx, 
I72.xx, I79.xx, I73.1x, I74.xx, 
I75.xx, I77.xx, I62.0x, I62.1x, 
I62.9x, I67.0, I67.2, I67.4, I67.5, 
I67.6, I67.7, I67.8, I67.9, I68.0, 
I68.2x, M30.xx, M31.xx, M32.1x, 
G45.4x, G46.0x, G46.1x, G46.2x, 
G46.3x, G46.4x, G46.5x, G46.6x, 
G46.7x, G46.8x,
-
Late effects of 
-
438.xx
I69.0x, I69.1x, I69.2x, I69.3x, 
-

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
cerebrovascular 
disease
I69.8x, I69.9x,
Cerebrovascular 
procedure 
Procedures related to
Carotid bypass, or
Cerebrovascular revascularization
39.28
00.61 - 00.65, 
38.11, 38.12
(no codes available)
-
CHF 
-
428.x, 398.91, 
402.01, 402.11, 
402.91, 404.01, 
404.11, 404.91, 
404.03, 404.13, 
404.93
I09.81, I11.0, I13.0, I13.2, I50.1, 
I50.20, I50.21, I50.22, I50.23, 
I50.31, I50.32, I50.33, I50.40, 
I50.41, I50.42, I50.43, I50.9
-
Peripheral vascular 
disease or surgery
Recorded diagnoses related to 
a)
peripheral vascular disease 
or procedures related to
b)
lower-extremity endarterectomy, 
stenting, angioplasty, or atherectomy,
c) Lower-extremity bypass, OR
d) Other peripheral vascular surgery
a) 440.20 –
440.24, 440.29 –
440.32, 440.3, 
440.4, 443.9
b) 38.18, 38.19
c) 39.25, 39.29
d) 38.08, 38.09, 
38.38, 
38.39,38.48, 
38.49, 39.5x, 
39.9x
Peripheral vascular disease: 
I70.2x, I70.3x, I70.4x, I70.5x, 
I70.6x, I70.7x, I70.9x
Lower extremity endarterectomy, 
stenting, angioplasty, or 
atherectomy:
(no ICD-10)
Lower-extremity bypass: 
(Aorta-iliac femoral bypass) 04.1x, 
04.7x,
Other peripheral vascular 
surgery:
(no ICD-10) 
-
Atrial fibrillation
-
427.3x
I48.0x, I48.1x, I48.2x, I48.3x, 
I48.4x, I48.9x
-

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
Other cardiac 
dysrhythmia 
-
427.xx, exclude 
427.5x (cardiac 
arrest) and 427.3x
I48.0x, I48.1x, I48.2x, I48.3x, 
I48.4x, I48.9x, I49.0x, I49.4x, 
I49.1x, I49.3x, I49.5x, I49.8x, 
I49.9, R00.1, 
Exclude I46.2x, I46.8x, I46.9 
(cardia arrest)
-
Cardiac conduction 
disorders 
-
426.xx
I44.0x, I44.1x, I44.2x, I44.3x, 
I44.4x, I44.5x, I44.6x, I44.7x, 
I45.0x, I45.1x, I45.4x, I45.2x, 
I45.3x, I45.5x, I45.6x, I45.8x, 
I45.9x
-
Other CV disease 
Including all registered CV events at any 
time prior to index date
390.xx -398.xx, 
420.xx -425.xx, 
441.xx -447.xx 
(except 442.1x, 
443.81, 443.9x)
I00-I09, I30-I43, I71-I75, I77, I79, 
M30, M31 (Except I72.2, I79.8, 
I73.9)
-
Edema 
-
782.3x
R60.0x, R60.1x, R60.9x
-
COPD 
-
491.xx, 492.xx, 
or 496.xx
J44
-
Asthma 
-
493.xx
J45.2x, J45.3x, J45.4x, J45.9xx
-
Obstructive sleep 
apnea 
-
327.23
G47.33
-
Pneumonia 
-
480.xx – 486.xx, 
487.0x, 507.xx
J12.0x, J12.1x, J12.2x, J12.8x, 
J12.3x, J12.9x, J13, J18.1x, J15, 
J15.1x, J14, J15.4x, J15.3, J15.2x, 
J15.8x, J15.5x, J15.6x, A48.1x, 
J15.9x, J15.7x, J16.0x, J16.8x, B25, 
-

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
A37.0x, A37.8x, A7.9x, A22.1x, 
B44.0x, J17, B77.8x, J17, J18.0x, 
J18.9x, J10.0x, J11.0X, J12.9x, 
J69.0x, J69.1, J69.8x
Renal dysfunction 
(non-diabetic)
Diagnoses related to
Acute renal disease, or
Chronic kidney disease, or
Hypertensive nephropathy, or
Miscellaneous Renal Insufficiency, or
Dialysis
Acute renal 
disease
572.4x, 580.xx, 
584.xx, 791.2x, 
791.3x
Chronic kidney 
disease:
585.xx
Hypertensive 
nephropathy:
403.xx, 404.xx
Miscellaneous 
Renal 
Insufficiency:
274.10, 440.1x, 
442.1x, 453.3x, 
581.xx, 593.xx, 
753.0x, 753.3x, 
866.00, 866.01, 
866.1x
Dialysis
Procedure:
39.95, 54.98
Diagnosis:
V56.0x, V56.8x, 
Acute renal disease: K76.7, N00.x, 
N01.x, N08, N17.x, R82.x,
Chronic kidney disease:
N18.5, N18.6 
Hypertensive nephropathy:
I12.9, I12.0, I13.0, I13.10, I13.11, 
I13.2
Miscellaneous Renal 
Insufficiency:
E082.1, E082.2, E082.9, N08, 
N02.8, N04.7, N04.8, N04.9, 
N28.83, N28.81, N28.1, N11.1, 
N13.0, N13.1, N13.5, N11.1, 
N13.8, N13.4, R80.2, N13.7, 
N13.71, N13.72x, N13.9, N28.9, 
N28.89, N28.82, N28.9, N29, 
Q60.0, Q60.1, Q60.2, Q60.3, 
Q60.4, Q60.5, Q60.6x, Q63.0, 
Q63.1, Q63.2, Q63.3, Q63.8, 
Q63.9, S37.001A, S37.002A, 
S37.009A, S37.011A, S37.012A, 
S37.019A, S37.021A, S37.022A, 
S37.029A
Dialysis:
Z99.2
-

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
V45.1x 
Acute renal disease 
-
572.4x, 580.xx, 
584.xx, 791.2x, 
791.3x
K76.7, N00.x, N01.x, N08, N17.x, 
R82.x, 
-
Chronic renal 
insufficiency
-
582.xx, 583.xx, 
585.xx, 586.xx, 
587.xx
N03.0, N03.1, N03.2, N03.3, 
N03.4, N03.5, N03.6, N03.7, 
N03.8, N03.9, N05.0, N05.1, 
N05.2, N05.3, N05.6, N05.7, 
N05.8, N05.9, N06.0, N06.1, 
N06.2, N06.3, N06.4, N06.5, 
N06.6, N06.9, N07.3, N07.4, 
N07.5, N07.7, N07.8, N07.9, N08, 
N14.0, N14.1, N14.2, N14.3, 
N14.4, N15, N15.8, N15.9, N16, 
N17.1, N17.2, N18.1, N18.2, 
N18.3, N18.4, N18.5, N18.6, 
N18.9, N19, N26.1, N26.9, E092.1, 
E092.2, M32.14, M32.15, M35.04, 
-
Chronic renal 
insufficiency without
chronic kidney disease
582.xx, 583.xx, 
585.9x, 586.xx, 
587.xx
(no ICD-10)
Chronic kidney 
disease Stage 1-2 
(no ICD-9)
(no ICD-10)

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
Chronic kidney 
disease stage 3-6
(no ICD-9) 
(no ICD-10)
Chronic kidney 
disease 
-
585.xx
N18.5, N18.6 
-
Chronic kidney 
disease stage 3-4 
-
585.3x-585.4x
N18.3, N18.4
-
Hypertensive 
nephropathy
-
403.xx, 404.xx
-
Miscellaneous Renal 
insufficiency
274.10, 440.1x, 
442.1x, 453.3x, 
581.xx, 593.xx, 
753.0x, 753.3x, 
866.00, 866.01, 
866.1x
E082.1, E082.2, E082.9, N08, 
N02.8, N04.7, N04.8, N04.9, 
N28.83, N28.81, N28.1, N11.1, 
N13.0, N13.1, N13.5, N11.1, 
N13.8, N13.4, R80.2, N13.7, 
N13.71, N13.72x, N13.9, N28.9, 
N28.89, N28.82, N28.9, N29, 
Q60.0, Q60.1, Q60.2, Q60.3, 
Q60.4, Q60.5, Q60.6x, Q63.0, 
Q63.1, Q63.2, Q63.3, Q63.8, 
Q63.9, S37.001A, S37.002A, 
S37.009A, S37.011A, S37.012A, 
S37.019A, S37.021A, S37.022A, 
S37.029A
Dialysis
Procedure:
39.95, 54.98 
Diagnosis:
V56.0x, V56.8x, 
V45.1x 
Z99.2 

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
Liver disease 
-
Diagnoses:
070.xx, 570.xx-
573.xx 456.0x-
456.2x, 576.8x, 
782.4x, 789.5x 
ICD-9 
Procedures:
39.1x, 42.91
B18, I85.0, I85.9, I86.4, I98.2, 
K70.0-K70.3, K70.4, K70.9, K71.1, 
K71.3-K71.5, K71.7, K72.1, K72.9, 
K73, K74, K76.0, K76.2-K76.4, 
K76.5, K76.6, K76.7K76.8, K76.9, 
Z94.4
-
Osteoarthritis 
Diagnoses related to polyarthrosis, 
coxarthrosis, gonarthrosis, arthrosis of first 
carpometacarpal joint, and another
arthrosis 
715.xx
M15.0, M15.1, M15.2, M15.3, 
M15.4, M15.8, M15.9, M16.0, 
M16.1, M16.2, M16.3, M16.4,
M16.5, M16.6, M16.7, M16.9, 
M17.0, M17.1, M17.2, M17.3, 
M17.4, M17.5, M17.9, M18.0, 
M18.1, M18.2, M18.3, M18.4, 
M18.5, M18.9,
M19.01, M19.02, M19.03, M19.04, 
M19.07, M19.11, M19.12, M19.13, 
M19.14, M19.17, M19.21, M19.22, 
M19.23, M19.24, M19.27, M19.90, 
M19.91, M19.92, M19.93, M19.9
-
Other arthritis, 
arthropathies and 
musculoskeletal pain
-
710.xx−714.xx, 
716.xx−719.xx, 
725.xx−729.xx 
(excluding 
729.2x)] 
M00-M08 (except M04.1), M11-
M14, M22-M25, M32-M36, M43.3, 
M43.4, M43.5, M60-M72 (except 
M62.830), M75-M79, (except 
M79.2), R26.2, R29.898, 
-
Dorsopathies 
-
720.xx-724.xx
M43.2, M43.6, M45-M54, M62.830
-
Bone fractures 
-
733.1x, 800.xx-
M80.0x, M80.8x, M84.4x, M84.5x, 
-

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
829.xx
M84.6x, M84.7x, M48.5x, S02.0X, 
S02.1x, S02. 11x, S02.2x, S02.3x, 
S02.9x, S02.4x, S06.5x, S02.6x, 
S02.9x, S06.33, S06.36, S06.4X, 
S06.5X, S06.6X, S06.8x, S06.9x, 
S12.9X, S12.0x,S12.1x, S12.2x, 
S12.3x, S12.4x, S12.5x, S12.6x,
S12.8x, S12.9, S22.0x, S32.0x, 
S12.0x, S12.1x, S12.2x, S12.3x, 
S14.1, S12.0x, S12.1x, S12.2x, 
S12.3x, S14.1x, S22.0x, S22.2x, 
S22.3x, S22.4x, S22.5x, S24.1x, 
S32.0x, S32.3x, S32.6x, S32.8x, 
S32.9x, S34.1x, S32.0x, S32.4x, 
S32.5x, S34.1x, S42.0x, S42.1x, 
S42.2x, S42.3x, S42.4x, S42.9x, 
S49.1x, S52.0x, S52.1x, S52.2x, 
S52.3x, S52.5x, S52.6x, S52.9x, 
S59.0x, S59.2x, S62.0x, S62.1x, 
S62.2x, S62.3x, S62.5x, S62.6x, 
S62.9x, S72.0x, S72.1x, S72.2x, 
S72.3x, S72.4x, S72.8x, S72.9x, 
S79.0x, S79.1x, S82.0x, S82.1x, 
S82.2x, S82.3x, S82.4x, S82.5x, 
S82.6x, S82.8x, S82.9x, S89.0x, 
S89.1x, S89.2x, S89.3x, S92.0x, 
S92.1x, S92.2x, S92.3x, S92.4x, 
S92.5x, S92.8x, S92.9x, S99.0x, 
S99.1x, S99.2x, T14.8

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
Falls
Diagnoses related to 
accidental falls or
history of falls
or dispensations/other records of the drug 
use of osteoporosis drugs 
a) E880.0x-
E888.9x 
b) V15.88
a) W00-W19
b) Z91.81
M05BA Bisphosphonates
M05BB 
Bisphosphonates, 
combinations1
G03XC01 Raloxifene
H05AA02 Teriparatide
H05BA Calcitonin 
preparations
Osteoporosis 
-
733.0x 
M80, M81
-
Hyperthyroidism 
-
242.1x, 242.3x, 
242.9x
E05.1, E05.2, E05.9
-
Hypothyroidism 
-
243.xx, 244.xx
E00, E01.8, E02, E03, E89.0
-
Other disorders of the 
thyroid gland
Excluding hyperthyroidism and 
hypothyroidism
240.xx – 246.xx, 
E01-E07
-
Depression 
-
293.83, 296.2x. 
296.3x, 298.0x, 
300.4x, 309.0x, 
309.1x, 309.28, 
311.xx
F03.6, F32 (except F32.8), F33 
(except F33.8), F34.1, F43.21, 
F43.23
-
Anxiety 
-
293.84, 300.0x, 
300.2x, 300.3x, 
309.24, 308.0x, 
309.81
F06.4, F40-F42 (except F42.4), 
F43.0, F43.1, F43.22
-
Sleep disorder 
-
307.4x, 327.0x, 
327.2x 780.5x, 
347.xx
F51 (except F51.13), G47 (except 
G47.4-G47.6) 
-

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
Dementia 
-
290.xx, 294.xx, 
330.xx, 331.xx
F01-F04, F05.1, F06.0, F06.1, 
F06.8, E75.0, E75.1, E75.23, 
E75.25, E75.29, E75.4, F84.2, G30, 
G31, G93.7, G93.9, 
-
Delirium 
-
290.11, 290.3x, 
290.41, 291.0x, 
292.81, 293.xx, 
348.3x, 349.82
F01.51, F03.90, F05, F1x.121, 
F1x.221 (except F17.221), F1x.231,
F1x.921, G93.4, I67.83, G92 
-
Psychosis 
-
290.8x, 290.9x, 
295.xx, 297.xx, 
298.xx, 299.xx, 
780.1x
F03.90, F20, F22-F29, F32.2, 
F32.3, F33.3, F44.89, F84 (except 
F84.2), R44.0, R44.2, R44.3 
-
Frailty
The sum of weights related to pre-
specified conditions (as in Kim et al. J 
Gerontol A Biol Sci Med Sci. 2018 Jun 
14;73(7):980-987)
-
Foot ulcer
707.1x, 440.23
I70.2x, I70.3x, I70.4x, I70.5x, 
I70.6x, I70.7x, L97.1x, L97.2x, 
L97.3x, L97.4x, L97.5x, L97.8x, 
L97.9x, 
Cellulitis or abscess of 
toe
680.7x, 682.7x
L02.61, L02.62, L02.63, L03.11, 
L03.12
Hypertension 1 code
401.xx-405.xx
I10.x, I11.x, I13.x, I15.x, I16.x, 
N26.2
Imaging
88.48, 88.77
B3.4x, B4.0x, B4.1x, B4.4x, 
Glaucoma or cataracts
365, 366
(not defined)

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
LABORATORY VALUES
HbA1c (%) 
As available in the data source
Low-density 
lipoprotein (LDL)
level (mg/dl)
As available in the data source
High-density 
lipoprotein (HDL)
level (mg/dl) 
As available in the data source
Total cholesterol 
(mg/dl) 
As available in the data source
Triglyceride level 
(mg/dl)
As available in the data source
Creatinine (mg/dl)
As available in the data source
Glomerular Filtration 
Rate 
(mL/min/1,73m2)
As available in the data source
BUN (mg/dl) 
As available in the data source
BNP 
As available in the data source
NT-proBNP 
As available in the data source
Prior/concomitant use of other antidiabetic drugs (12 months preceding index date and at index date)
N antidiabetic 
substances at index 
date
N antidiabetic substances (including study 
drugs listed in Table 3 and other 
antidiabetic substances) on the day of 
initiation of the study drug
Unique substances in the 
ATC class A10 drugs 
used in diabetes. Fixed-
dose combination 
products with multiple 

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
substances count as 
multiple drugs, e.g. 
empagliflozin+metformin 
results in 2 substances
Naive new use of 
antidiabetic drugs
No use of any antidiabetic drug in the prior 
12 months
No use of drugs in the 
ATC class A10 drugs 
used in diabetes, apart 
from the index drug
Initiation of the study 
drug 
(empagliflozin/any 
SGLT-2 inhibitor/any 
DPP-4 inhibitor) as 
monotherapy 
Study drug (empagliflozin/any SGLT-2 
inhibitor/ any DPP-4 inhibitor) initiated as 
monotherapy, i.e., no filled dispensation/
no other records of the drug use of any 
anti-diabetic drugs in the 12 months prior 
to drug initiation AND no concomitant 
initiation of any anti-diabetic drugs at 
index date
For study drugs: see
Table 3, excluding the 
listed fixed-dose 
combinations
For any anti-diabetic 
drugs: A10 drugs used in 
diabetes
Dual therapy with 
metformin (without 
the use of other 
antidiabetic drugs)
≥2 filled dispensations/other records of the 
drug use of metformin in the 183 days
prior to index date and current use (i.e. 
days’ supply overlap) at index date AND 
no filled dispensations or other records of 
the drug use of other drugs used in 
diabetes in the 12 months prior to the 
index date
A10BA02 metformin
For other antidiabetic 
drugs: A10 drugs used in 
diabetes

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
Concomitant initiation 
or current use of other 
antidiabetic drugs
≥1 filled dispensation/any other record of 
the drug use of other antidiabetic drugs at 
index date of the drug of interest 
OR 
≥1 filled dispensation/any other record of 
the drug use of other antidiabetic drugs 12 
months prior to index date with current use 
at index date (i.e. days of supply overlap 
with index date) 
A10 drugs used in 
diabetes
and
The drugs/drug classes 
listed below* separately
Past use of other 
antidiabetic drugs
≥1 filled dispensation/any other record of 
the drug use of other antidiabetic drugs 12 
months prior to index date without current 
use at index date (i.e. NO overlapping days 
of supply with index date)
A10 drugs used in 
diabetes
and
The drugs/drug classes 
listed below* separately
Metformin*
(excluding fixed-dose combinations with 
metformin and the study drugs listed in 
Table 3; including fixed-dose 
combinations with metformin and other 
drugs)
A10BA02 metformin
A10BD05 metformin and 
pioglitazone
A10BD03 metformin and 
rosiglitazone3
Sulfonylureas 2nd
generation*
Glimepiride, glipizide, glibornuride (also 
known as glyburide)
A10BB12 glimepiride
A10BB07 glipizide
Glucagon-like 
peptide-1 receptor 
agonists*
-
A10BJ Glucagon-like 
peptide-1 analog
Thiazolidinediones*
-
A10BG 
Thiazolidinediones
A10BD03 metformin and 

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
rosiglitazone
A10BD04 glimepiride 
and rosiglitazone
A10BD05 metformin and 
pioglitazone
A10BD06 glimepiride 
and pioglitazone
Meglitinides*
-
A10BX02 repaglinide
A10BX03 nateglinide
Insulin*
-
A10A insulins and 
analogs
Alpha-glucosidase 
inhibitors*
-
A10BF Alpha-
glucosidase inhibitors
Any use of 
pramlintide
≥1 filled dispensation/any other record of
the drug use of pramlintide 12 months 
prior to the index date
Any use of 1st
generation 
sulfonylureas
≥1 filled dispensation/any other record of 
the drug use of 1st generation 
sulfonylureas 12 months prior to the index 
date (acetohexamide, chlorpropamide, 
tolazamide, tolbutamide) in the 12-month 
period prior to the day of initiation of the 
drug of interest
A10BB03 tolbutamide
Prior use of other drugs (12 months preceding index date
Angiotensin-
converting-enzyme
inhibitor
≥1 filled dispensation/any other record of 
the drug use
C09A Angiotensin-
converting-enzyme
inhibitors, plain

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
C09B Angiotensin-
converting-enzyme
inhibitors, combinations
Angiotensin II 
receptor blocker
≥1 filled dispensation/any other record of 
the drug use
C09C angiotensin ii 
antagonists, plain
C09D angiotensin ii 
antagonists, 
combinations
Beta-blocker 
≥1 filled dispensation/any other record of 
the drug use
C07 beta-blocking agents
Calcium channel 
blocker 
≥1 filled dispensation/any other record of 
the drug use
C08 calcium channel 
blockers
C07FB Beta-blocking 
agents and calcium 
channel blockers
C09BB Angiotensin-
converting-enzyme 
inhibitors and calcium 
channel blockers
C09DB Angiotensin II 
antagonists and calcium 
channel blockers
Thiazides
≥1 filled dispensation/any other record of 
the drug use
C03A low-ceiling 
diuretics, thiazides
Loop diuretics 
≥1 filled dispensation/any other record of 
the drug use
C03C high-ceiling 
diuretics
Other diuretics 
≥1 filled dispensation/any other record of 
the drug use
C03D potassium-sparing 
agents

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
Nitrates
≥1 filled dispensation/any other record of 
the drug use
Including glyceryl trinitrate (also known as 
nitroglycerin), isosorbide dinitrate, 
isosorbide mononitrate, ranolazine
C01DA02 glyceryl 
trinitrate
C01DA08 isosorbide 
dinitrate
C01DA14 isosorbide 
mononitrate
C01EB18 ranolazine
Other hypertension 
drugs 
≥1 filled dispensation/any other record of 
the drug use
Including doxazosin, eplerenone, prazosin, 
terazosin, clonidine, guanabenz (no ATC 
code), guanadrel (no ATC code), 
guanethidine, guanfacine, hydralazine, 
methyldopa, metirosine (also known as 
metyrosine), reserpine, minoxidil, aliskiren
C02CA04 doxazosin
C03DA04 eplerenone
C02CA01 prazosin
G04CA03 terazosin
C02AC01 clonidine
C02AC02 guanfacine
C02DB02 hydralazine
C09XA02 aliskiren
C09XA52 aliskiren and 
hydrochlorothiazide
Digoxin 
≥1 filled dispensation/any other record of 
the drug use
C01AA05
Valsartan and 
sacubitril
≥1 filled dispensation/any other record of 
the drug use
C09DX04 
Antiarrhythmic drugs 
≥1 filled dispensation/any other record of 
the drug use
C01B antiarrhythmics, 
class I and III
COPD or asthma 
medications 
≥1 filled dispensation/any other record of 
the drug use
Including: Fluticasone/salmeterol (fixed 
combo), budesonide/formoterol (fixed 
combo), mometasone/formoterol (fixed 
R03AK06 salmeterol and 
fluticasone
R03AK07 formoterol and 
budesonide 
R03AC13 formoterol

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
combo), aformoterol, formoterol, 
salmeterol, salbutamol (also known as 
albuterol/levalbuterol),orciprenaline (also 
known as metaproterenol), pirbuterol, 
terbutaline, ipratropium, tiotropium, 
theophylline, montelukast, zafirlukast, 
zileuton (no ATC code), aclidinium, 
indacaterol, olodaterol, umeclidinium
R03AC12 salmeterol
R03AC02 salbutamol
R03CC03 terbutaline1
R01AX03 ipratropium 
bromide2
R03BB01 ipratropium 
bromide
R03BB04 tiotropium 
bromide
R03DA04 theophylline
R03DC03 montelukast
R03DC01 
zafirlukast2,3,4
R03BB05 aclidinium 
bromide
R03AL05 formoterol and 
aclidinium bromide
R03AC18 indacaterol
R03AC19 olodaterol
R03BB07 umeclidinium 
bromide
R03AL01 fenoterol and 
ipratropium bromide1,2,3
R03AL02 salbutamol and 
ipratropium bromide2
R03AL03 vilanterol and 
umeclidinium bromide
R03AL04 indacaterol 
and glycopyrronium 
bromide

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
R03AL05 formoterol and 
aclidinium bromide 
R03AL06 olodaterol and 
tiotropium bromide
R03AL08 vilanterol, 
umeclidinium bromide,
and fluticasone furoate
R03AL09 formoterol, 
glycopyrronium bromide,
and beclometasone
Statin 
≥1 filled dispensation/any other record of 
the drug use
C10AA HMG CoA 
reductase inhibitors
C10BA HMG CoA 
reductase inhibitors in 
combination with other 
lipid modifying agents
C10BX HMG CoA 
reductase inhibitors, 
other combinations
PCSK-9 inhibitors
≥1 filled dispensation/any other record of 
the drug use
C10AX13 Evolocumab
Bococizumab
C10AX14 Alirocumab
Other lipid-lowering 
drugs, excluding 
statins
≥1 filled dispensation/any other record of 
the drug use
C10 lipid modifying 
agents, excluding
C10AA HMG CoA 
reductase inhibitors
C10BA HMG CoA 
reductase inhibitors in 
combination with other 

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
lipid modifying agents
C10BX HMG CoA 
reductase inhibitors, 
other combinations
Antiplatelet 
≥1 filled dispensation/any other record of 
the drug use
Including Aspirin alone, clopidogrel, 
prasugrel, ticlopidine, aspirin-
dipyridamole, dipyridamole alone, 
cilostazol, ticagrelor
B01AC06 acetylsalicylic 
acid
B01AC04 clopidogrel
B01AC22 prasugrel
B01AC05 ticlopidine
B01AC07 dipyridamole
B01AC23 cilostazol
B01AC24 ticagrelor
Anticoagulants 
≥1 filled dispensation/any other record of 
the drug use
Including warfarin, dabigatran, 
rivaroxaban, apixaban
B01AA03 warfarin 
B01AE07 dabigatran 
etexilate
B01AF01 rivaroxaban
B01AF02 apixaban
Heparin and other 
low-molecular-weight 
heparins
≥1 filled dispensation/any other record of 
the drug use
Including heparin (including tinzaparin) 
dalteparin, enoxaparin
B01AB Heparin group
B01AE07 dabigatran 
etexilate
Nonsteroidal anti-
inflammatory drugs
≥1 filled dispensation/any other record of 
the drug use
M01A anti-inflammatory 
and antirheumatic 
products, non-steroids
Oral corticosteroids 
≥1 filled dispensation/any other record of
the drug use of oral formulations
Including cortisone, hydrocortisone, 
prednisone, prednisolone, 
H02AB10 cortisone
H02AB09 
hydrocortisone
H02AB07 prednisone2

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
methylprednisolone, triamcinolone, 
dexamethasone, betamethasone
H02AB06 prednisolone
H02AB04 
methylprednisolone
H02AB08 triamcinolone 
H02AB02 
dexamethasone
H02AB01 betamethasone
Bisphosphonates 
≥1 filled dispensation/any other record of 
the drug use
M05BA Bisphosphonates
M05BB 
Bisphosphonates, 
combinations
Opioids 
≥1 filled dispensation/any other record of 
the drug use
N02A
Antidepressants 
≥1 filled dispensation/any other record of 
the drug use
N06A
Antipsychotics 
≥1 filled dispensation/any other record of 
the drug use
N05A
Anticonvulsants 
≥1 filled dispensation/any other record of 
the drug use
N03A
Lithium 
≥1 filled dispensation/any other record of 
the drug use
N05AN01
Benzodiazepines 
≥1 filled dispensation/any other record of 
the drug use
N05BA Benzodiazepine 
derivatives
N05CD Benzodiazepine 
derivatives
Other 
anxiolytics/hypnotics 
≥1 filled dispensation/any other record of 
the drug use
N05CF02 zolpidem
N05CF01 zopiclone

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
Including eszopiclone, zaleplon, zolpidem, 
chloral hydrate, diphenhydramine, 
doxylamine, ethchlorvynol, glutethimide, 
methaqualone, buspirone
R06AA02 
diphenhydramine1,2
R06AA09 doxylamine3
N05BE01 buspirone
Agents for dementia 
≥1 filled dispensation/any other record of 
the drug use
N06D anti-dementia 
drugs
Anti-Parkinson agents
≥1 filled dispensation/any other record of 
the drug use
N04 anti-Parkinson drugs
HEALTHCARE RESOURCE UTILIZATION COVARIATE (12 months preceding index date)
Combined 
comorbidity score
The sum of weights related to pre-
specified comorbidities (as in Gagne et al. 
J Clin Epidemiol. 2011 Jul;64(7):749-59)
Conditions with weight of 5:
Metastatic cancer
Conditions with weight of 2:
Congestive heart failure; 
dementia; 
renal failure; 
weight loss
Conditions with weight of 1:
Hemiplegia; 
alcohol abuse; 
any tumor; 
cardiac arrhythmias; 
chronic pulmonary disease; 
a)
196.x–
199.x
b)
402.01, 
402.11, 
402.91, 
425.x, 
428.x, 
429.3
c)
290.x, 
331.0, 
331.1, 
331.2
d)
403.11, 
403.91, 
404.12, 
404.92, 
585.x, 
586.x, 
a)
C45.9, C77.x-C80.x
b)
A18.84, I09.9, I11.0, I13.0, 
I13.2, I25.5, I42.x, I43.x, 
I50.x, I51.7, P29.0
c)
F01.x–F03.x, F05, G30.x, 
G31.01, G31.09, G31.1
d)
I12.0, I13.x, N03.2–N03.7, 
N05.2– N05.7, N18.x, N19.x, 
N25.0, Z39.32, Z48.22, 
Z49.0x, Z49.31, Z91.15, 
Z94.0, Z99.2
e)
E40.x-E46.x, E64.0, R63.4, 
R64
f)
G04.1, G11.4, G80.1, G80.2, 
G81.x, G82.x, G83.x
g)
F10.x, E52, G62.1, I42.6, 
K29.2x, K70.0, K70.3x, 

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
coagulopathy; 
complicated diabetes; 
deficiency anemias; 
fluid and electrolyte disorders; 
liver disease; 
peripheral vascular disorder; 
psychosis; 
pulmonary circulation disorders;
Conditions with weight of -1
HIV/AIDS; 
hypertension
V42.0, 
V45.1, 
V56.0, 
V56.8
e)
260.x–
263.x
f)
342.x, 
344.x
g)
291.1, 
291.2, 
291.5, 
291.8, 
291.9, 
303.9-
303.93, 
305.0-
305.03, 
V11.3
h)
140.x–
171.x, 
174.x–
195.x, 
200.x–
208.x, 
273.0, 
273.3, 
V104.6
i)
426.10, 
K70.9, T51.x, Z71.4x, Z65.8
h)
C00.x-C26.x, C30.x–C34.x, 
C37.x-C41.x, C43.x, C45.x–
C58.x, C60.x– C75.x, C76.x, 
C81.x-94.3x, C94.8x, C95.x, 
C96.0-C96.4, C96.9, C96.A, 
C96.Z, D45, D89, Z85.46
i)
I44.0, I44.1, I44.3x-145.2, 
I45.4-I45.8x, I45.9, I47.x–
I49.x, R00.0, R00.1, R00.8, 
T82.1x, Z45.0x, Z95.0, 
Z95.810, Z95.818, Z95.9
j)
I26.0x, I27.2-I27.9, J40.x-
J47.x, J60.x–J67.x, J68.4, 
J70.1, J70.3
k)
D65.x-D68.x, D69.1, D69.3–
D69.6
l)
E10.2x–E10.8, E11.2x–
E11.8, E12.2x– E12.8, 
E13.2x–E13.8x
m) D50.1-D50.9, D51.x–D53.x, 
D64.9
n)
E22.2, E86.x, E87.x
o)
B18.x, I85.x, I86.4, K70.x, 
K71.1, K71.3–K71.5, K71.7, 
K72.1x, K72.9.x, K73.x-

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
426.11, 
426.13, 
426.2-
426.4, 
426.50-
426.53, 
426.6-
426.8, 
427.0, 
427.2, 
427.31, 
427.6, 
427.9, 
785.0, 
V45.0, 
V53.3
j)
415.0, 
416.8, 
416.9, 
491.x–
494.x, 
496.x
k)
286.0-
286.9, 
287.1, 
287.3–
287.5
l)
250.4–
250.73, 
K74.x, K75.4, K75.81, 
K76.0, , K76.2–K76.9, 
Z48.23, Z94.4
p)
E08.51, E08.52, E09.51, 
E09.52, E10.51, E10.52, 
E11.51, E13.51, E13.52, 
I67.0, I70.x, I71.x, I73.1, 
I73.8x, I73.9, I77.1, I77.71-
I77.74, I177.79, I79.x, K55.1, 
K55.8, K55.9, Z95.82x, 
Z95.9
q)
F20.x, F22-25.x, F28.x, 
F29.x, F30.x-F33.x, F34.8, 
F34.9, F39.x, F44.89, F84.3 
r)
I26.x, I27.x, I28.0, I28.8, 
I28.9 
s)
B20.x
t)
I10.x, I11.x–I13.x, I15.x, 
N26.2

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
250.90-
250.93
m) 280.1–
281.9, 
285.9
n)
276.x
o)
070.32, 
070.33, 
070.54, 
456.0, 
456.1, 
456.20, 
456.21, 
571.0, 
571.2, 
571.3, 
571.40-
571.49, 
571.5, 
571.6, 
571.8, 
571.9, 
572.3, 
572.8, 
V42.7
p)
440.x, 
441.2, 
441.4, 

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
441.7, 
441.9, 
443.1–
443.9, 
447.1, 
557.1, 
557.9, 
V43.4
q)
295.x-
298.99, 
299.1, 
299.11
r)
416.x, 
417.9
s)
042.x–
044.x
t)
401.1, 
401.9, 
402.10, 
402.90, 
404.10, 
404.90, 
405.11, 
405.19, 
405.91, 
405.99

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
Total N distinct 
diagnosis codes
3rd digit level ICD diagnoses
Number of different 
medications
As available in the data source, for 
example number of unique 7-digit ATC 
codes
Any hospitalization
As available in the data source
Any hospitalization 
within prior 30 days
As available in the data source
Any hospitalization 
during prior 31-365 
days
As available in the data source
Number of 
hospitalizations
As available in the data source
Number of hospital 
days
As available in the data source
Number of emergency 
department visits
As available in the data source
Number of office 
visits
As available in the data source
Endocrinologist visit 
As available in the data source
Endocrinologist visit 
in 30 days prior
As available in the data source
Endocrinologist visit 
in 31 to 365 days prior
As available in the data source
Number of 
As available in the data source

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
endocrinologist visits
Internal medicine (IM) 
/ family medicine 
(FM) visits
As available in the data source
Number of IM/FM 
visits
As available in the data source
IM/FM visit (30 days 
prior)
As available in the data source
IM/FM visit (31 to 
365 days prior)
As available in the data source
Cardiologist visit 
As available in the data source
Number of 
cardiologist visits
As available in the data source
Cardiologist visit (30 
days prior)
Cardiologist visit (31 
to 365 days prior)
Electrocardiogram 
-
89.51, 89.52
4A.020FZ, 4A.02XFZ, 4A.0204Z, 
4A.02X4A, 4A.02X4Z
Number 
electrocardiograms 
received
-
89.51, 89.52
Use of glucose test 
strips
As available in the data source

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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
Number of HbA1c
tests ordered
As available in the data source
Number of glucose 
tests ordered
As available in the data source
Number of lipid tests 
ordered
As available in the data source
Number of creatinine 
tests ordered
As available in the data source
Number of BUN tests 
ordered
As available in the data source
Number of tests for 
microalbuminuria
As available in the data source
Cost covariates (12 months preceding index date)
The total cost of care 
Total charges for inpatient, outpatient, and 
pharmacy services
Inpatient cost 
Total charges for inpatient services
Total CV-related 
inpatient cost
Total charges for inpatient services for 
hospitalization with a primary discharge 
diagnosis of a cardiovascular condition
Cardiovascular 
condition (ICD-9 
390-459)
Cardiovascular condition (ICD-10 
I00 to I99) 

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Protocol for non-interventional studies based on existing data
BI Study Number 1245.195
c26457869-02
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001-MCS-90-124_RD-01 (4.0)
Covariate
Definition (when applicable)
ICD-9
ICD-10
ATC
Total non-CV-related 
inpatient cost 
Total charges for inpatient services for 
hospitalization with a primary discharge 
diagnosis of a non-cardiovascular 
condition
Non-
cardiovascular 
condition (any 
ICD-9 expect for 
390-459)
Non-cardiovascular condition (any 
ICD-10 expect for I00 to I99)
Total outpatient cost 
Total charges for outpatient services
Total CV-related 
outpatient cost
Total charges for outpatient services for 
physician visits associated with a 
cardiovascular diagnosis
Cardiovascular 
diagnosis (ICD-9 
390-459)
Cardiovascular condition (ICD-10 
I00 to I99) 
Total non-CV-related 
outpatient cost
Total charges for outpatient services for 
physician visits associated with a non-CV 
diagnosis
Non-CV 
diagnosis (any 
ICD-9 except for 
390-459)
Non-cardiovascular condition (any 
ICD-10 expect for I00 to I99)
Total pharmacy cost 
Total charges for pharmacy services
Total pharmacy cost 
for antidiabetic 
medications
Total charges associated with the use of 
antidiabetic medications
Total pharmacy cost 
for non-antidiabetic 
medications
Total charges associated with the use of 
medications other than antidiabetics
AIDS=acquired immunodeficiency syndrome; ATC=Anatomical Therapeutic Chemical; BNP=B-type natriuretic peptide; BUN=blood urea nitrogen; CABG=coronary artery 
bypass grafting; CHF=congestive heart failure; COPD=chronic obstructive pulmonary disease; CV=cardiovascular; GLP=glucagon-like peptide; HbA1c=glycated 
hemoglobin A1c; HIV=human immunodeficiency virus; ICD-9=International Classification of Diseases, 9th revision; ICD-10=International Classification of Diseases, 10th
revision; IM=internal medicine; MI=myocardial infarction; FM=family medicine; NT=N-terminal; PTCA=percutaneous transluminal coronary angioplasty.

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Protocol for non-interventional studies based on existing data
BI Study Number 1245.195
c26457869-02
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001-MCS-90-124_RD-01 (4.0)
ANNEX 8. DIAGNOSIS CODES FOR OTHER VARIABLES REQUIRED 
FOR ANALYSES
Diagnosis
ICD-9
ICD-10
Malignant neoplasm 
140.xx-208.xx (except 173.xx, non-
melanoma skin cancer)
C00.x-C96.x, D03.0x, Z85 
(except C44, C4A, C7A, C7B)
ICD-9=International Classification of Diseases, 9th revision; ICD-10=International Classification of Diseases, 10th revision.

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
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Title: 
 
 
 
 
                                                                                                                   
 
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c26457869
2.0
1245-0195-protocol-v1-0-final 2018-10-31-clean-2018-11-02
Multi-country non-interventional study on the effectiveness and safety of
Empagliflozin in adult patients with type 2 diabetes in Europe and Asia
Approval-Team Member Medicine
15 Oct 2019 09:46 CEST
Approval
Safety Evaluation
Therapeutic Area
15 Oct 2019 11:02 CEST
Author-On behalf of Coauthor
15 Oct 2019 16:06 CEST
Approval-On behalf of
or 
or
15 Oct 2019 19:06 CEST

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