Active Surveillance Research Program for the Assessment of the Safety and the Effectiveness of Linagliptin
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim

ABCD
TITLE PAGE
TITLE PAGE
Protocol for observational studies based on existing data
Document Number:
c02611829-01
BI Study Number:
1218.163
BI Investigational
Product(s):
Linagliptin
Title:
Active surveillance research program for the assessment of the 
safety and the effectiveness of linagliptin
Protocol version 
identifier:
1
Date of last version of 
protocol:
N/A
PASS:
Yes
Voluntarily initiated with the aim to better understand the 
comparative safety and effectiveness of oral hypoglycemic 
agents.
EU PAS register 
number:
To be completed 
Active substance:
Linagliptin
Medicinal product:
Trajenta
Product reference:
EU/1/11/707/1-11
Procedure number:
N/A
Marketing 
authorization holder(s):
Boehringer Ingelheim GmbH
Joint PASS:
No 
Research question and 
objectives:
This protocol is for a series of comparative effectiveness and 
safety analyses within periodically updated cohorts of patients 
initiating linagliptin, other DPP-4 inhibitors, and other oral 
hypoglycemic medications, followed longitudinally for the 
occurrence of a variety of health outcomes.
Objectives:
1) To conduct a multi-year surveillance program that establishes 
and periodically updates initiator cohorts of linagliptin, 
within-class comparators (saxagliptin, sitagliptin, alogliptin), 
and out-of-class comparators (glitazones, 2nd generation of 
sulfonylureas (SUs)), and longitudinally follow them for the 
incidence of a variety of health outcomes (e.g.cardiovascular, 
 renal 
impairment  
).

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2) To conduct direct comparisons over time among  
hypoglycemic agents (linagliptin versus other DPP-4, 
glitazones 2nd generation of SUs) and quantify the association 
between hypoglycemic choice and the occurrence of specific 
outcomes of interest.
The primary outcomes of interest will be the occurrence of a 
major cardiovascular event (defined as composite of coronary 
revascularization, acute coronary syndrome hospitalization, 
ischemic and hemorrhagic stroke) and the individual components 
of the composite cardiovascular outcome. Heart failure 
hospitalization, incident end-stage renal disease and acute renal 
failure will be considered secondary outcomes of interest.  
Country(-ies) of study:
US
Author:
 
 
Marketing authorisation 
holder(s):
MAH contact person:
EU-QPPV:
Signature of EU-QPPV:
The signature of the EU-QPPV is provided electronically
Date:
Jul 03, 2014
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TABLE OF CONTENTS
TITLE PAGE ..................................................................................................................1
TABLE OF CONTENTS ................................................................................................3
LIST OF TABLES ..........................................................................................................5
LIST OF FIGURES.........................................................................................................6
1.
LIST OF ABBREVIATIONS................................................................................7
2.
RESPONSIBLE PARTIES ....................................................................................9
3.
ABSTRACT.........................................................................................................10
4.
AMENDMENTS AND UPDATES.....................................................................14
5.
MILESTONES.....................................................................................................15
6.
RATIONALE AND BACKGROUND................................................................17
7.
RESEARCH QUESTION AND OBJECTIVES..................................................18
8.
RESEARCH METHODS.....................................................................................19
8.1
STUDY DESIGN............................................................................................19
8.2
SETTING ........................................................................................................19
8.2.1
Subjects....................................................................................................19
8.2.2
Cohort formation .....................................................................................23
8.3
VARIABLES...................................................................................................24
8.3.1
Exposure..................................................................................................24
8.3.2
Outcomes.................................................................................................28
8.3.3
Covariates ................................................................................................34
8.4
DATA SOURCES...........................................................................................34
8.5
STUDY SIZE ..................................................................................................35
8.6
DATA MANAGEMENT................................................................................39
8.7
DATA ANALYSIS .........................................................................................39
8.7.1
Main Analysis..........................................................................................40
8.7.3
Bias ..........................................................................................................43
8.8
QUALITY CONTROL ...................................................................................43
8.9
LIMITATIONS OF THE RESEARCH METHODS ......................................43
8.10
OTHER ASPECTS..........................................................................................44
9.
PROTECTION OF HUMAN SUBJECTS...........................................................45
10.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS .......................................................................................................46
11.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTs
..............................................................................................................................47

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12.
REFERENCES.....................................................................................................48
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS ..............................................53
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS.................................. 54
ANNEX 3. ADDITIONAL INFORMATION ..............................................................60
ANNEX 3.1 OTHER HYPOGLYCEMIC AGENTS.............................................60
ANNEX 3.2 DEFINITIONS OF STUDY COVARIATES .................................... 62
ANNEX 3.3 GENERAL CONSIDERATIONS FOR DIABETES 
MELLITUS TYPE 2  THERAPY...........................................................79
ANNEX 3.4 EXAMPLE STUDY SHELL TABLES............................................. 83
ANNEX 3.5  EXAMPLE STUDY FIGURES........................................................ 94

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LIST OF TABLES
Table 1    Cohort-defining non-insulin hypoglycemic medications .............................. 17
Table 2    Exclusion criteria: Definition of secondary diabetes, cancer history, 
ESRD, HIV, and organ transplant .......................................................... 21
Table 3    Study comparisons of interest and planned analyses ..................................... 25
Table 4    Variations in exposure risk window definitions – AT approach.................... 27
Table 5    Variations in exposure risk window definitions – ITT approach................... 28
Table 6    Outcome definitions....................................................................................... 29
Table 7    UnitedHealth and MarketScan databases Pilot Data, New Users  of 
DPP-4 inhibitors with T2DM diagnosis , in the period 
May 2011 – December 2012 .................................................................. 35
Table 8    Projected minimum detectable relative rates by reporting period with 
a power of 80%....................................................................................... 36

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LIST OF FIGURES
Figure 1
Patient Selection Flow Chart for initial time-block................................ 24
Figure 2
Sequential matched cohort study schematic........................................... 40

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1.
LIST OF ABBREVIATIONS
ACS
Acute Coronary Syndrome
AES
Advanced Encryption Standard
AGI
Alpha-Glucosidase Inhibitors
AMI
Acute Myocardial Infarction
ARB
Angiotensin Receptor Blocker
ARF
Acute Renal Failure
ASCVD
Atherosclerotic Cardiovascular Disease
BI
Boehringer Ingelheim International, GmbH
CABG
Coronary Artery Bypass Graft
CHF
Congestive Heart Failure
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
COX-2
Cyclooxygenase-2
CPT-4
Common Procedural Terminology, 4th Edition
Cr
Creatinine
DM
Diabetes Mellitus
DPP-4
Dipeptidyl Peptidase-4
dx
Diagnosis-Related Group
ECG
Electrocardiogram
EC-IC
Extracranial-Intracranial
eGFR
Estimated Glomerular Filtration Rate
ESKD
End-stage Kidney Disease
ESRD
End-stage Renal Disease
FDA
United States Food and Drug Administration
FPG
Fasting Plasma Glucose
GFR
Glomerular Filtration Rate
GLP-1
Glucagon-like peptide-1
HbA1c
Hemoglobin A1c (Glycosylated Hemoglobin)
HCPC
Healthcare Common Procedure Coding
HDL
High-density Lipoprotein
hdPS
High-dimensional Propensity Score
HIV
Human Immunodeficiency Virus
HIT
Heparin-Induced Thrombocytopenia
HONK
Hyperosmolar Hyperglycemic Nonketotic Syndrome
HR
Hazard Ratio
ICD-9
International Classification of Diseases, Ninth Revision

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IRB
Internal Review Board
ITT
Intention-to-Treat
LDL
Low-density Lipoprotein
LMWH
Low Molecular Weight Heparin
LOS
Length of Stay
MDRD
Modification of Diet in Renal Disease
MI
Myocardial Infarction
NOS
Not Otherwise Specified 
NPH
Neutral Protamine Hagedorn
NPV
Negative Predictive Value
OAD
Oral Antidiabetic
OTC
Over The Counter
Pap
Papanicolaou
PCI
Percutaneous Coronary Intervention
PCOS
Polycystic Ovary Syndrome
PPV
Positive Predictive Value
PS
Propensity Score
PSA
Prostate-Specific Antigen
PTCA
Percutaneous Transluminal Coronary Angioplasty
PVD
Peripheral Vascular Disease
RR
Relative Risk
SCr
Serum Creatinine
SD
Standard Deviation
s.e.
Standard Error
T1DM
Type 1 Diabetes Mellitus
T2DM
Type 2 Diabetes Mellitus
TB
Terabytes
TZD
Thiazolidinedione
US
United States
VLDL
Very low-density lipoprotein

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2.
RESPONSIBLE PARTIES

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3.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Trajenta
Name of active ingredient:
Linagliptin
Protocol date:
Study
number:
Version/Revision: 1
Version/Revision 
date:
03 Jul 2014
1218.163
Title of study:
Active surveillance research program for the assessment of the safety 
and the effectiveness of linagliptin
Rationale and 
background:
Dipeptidyl peptidase-4 (DPP-4) inhibitors, including linagliptin, 
saxagliptin, alogliptin and sitagliptin, are a new class of oral 
hypoglycemic agents approved in the United States. They are indicated
for use as an adjunct to diet and exercise to improve glycemic control 
in adults with type 2 diabetes mellitus (T2DM). Evidence to date 
suggests that these drugs offer advantages over older therapies in that 
they are weight-neutral, are associated with a minimal risk of 
hypoglycemia, and can be administered with once-daily dosing. 
Linagliptin offers a further advantage in that its dose does not need to 
be adjusted based on renal or hepatic function. While there do not 
appear to be contraindications (except for hypersensitivity to the active 
ingredient or any of the excipients) to the use of Linagliptin, the long-
term safety and effectiveness have not been well characterized.
Given the high prevalence of T2DM, it is important to understand the 
comparative safety and effectiveness of oral hypoglycemic agents. 
This protocol is for a series of comparative effectiveness and safety 
analyses within periodically updated cohorts of patients initiating 
linagliptin, other DPP-4 inhibitors, and other oral hypoglycemic 
medications, followed longitudinally for the occurrence of a variety of 
health outcomes. The initial analyses will be based on data from May 
2011 through June 2013 and will be sequentially updated every 6 
months through December 2016.
Research question 
and objectives:
This protocol is for a series of comparative effectiveness and safety 
analyses within periodically updated cohorts of patients initiating 
linagliptin, other DPP-4 inhibitors, and other oral hypoglycemic 
medications, followed longitudinally for the occurrence of a variety of 
health outcomes.
Objectives:
1.
To conduct a multi-year surveillance program that establishes 
and periodically updates initiator cohorts of linagliptin, within-
class comparators (saxagliptin, sitagliptin, alogliptin), and out-
of-class comparators (glitazones, 2nd generation of 
sulfonylureas (SUs)), and longitudinally follow them for the 
incidence of a variety of health outcomes (i.e. cardiovascular, 
 renal 
impairment  
).

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2.
To conduct direct comparisons over time among hypoglycemic 
agents (linagliptin versus other DPP-4 inhibitors, glitazones 
2nd generation of SUs) and quantify the association between 
hypoglycemic choice and the occurrence of specific outcomes 
of interest.
The primary outcomes of interest will be the occurrence of a major 
cardiovascular event (defined as composite of coronary 
revascularization, acute coronary syndrome hospitalization, ischemic 
and hemorrhagic stroke) and the individual components of the 
composite cardiovascular outcome. Heart failure hospitalization, 
incident end-stage renal disease and acute renal failure will be 
considered secondary outcomes of interest.  We will use multiple 
comparators because there are several potential treatment alternatives 
to linagliptin for patients with T2DM.
Although linagliptin is the only DPP-4 inhibitor that does not require 
dose adjustment for severe renal impairment, within-class comparators, 
i.e. other dipeptidyl peptidase-4 (DPP-4) inhibitors, are expected to 
have utilization patterns similar to linagliptin and to be prescribed to 
patients with similar clinical profile
Out-of-class comparators, i.e. second-generation sulfonylureas and 
pioglitazone, will be considered in order to investigate between-class 
effects. 2nd generation sulfonylureas and glitazones are oral 
hypoglycemics and are not usually used as 1st-line therapy. Therefore, 
they may be more commonly used as an alternative to linagliptin than 
other treatment options such as glucagon-like peptide-1 (GLP-1) 
receptor agonists or metformin.  SGLT2 inhibitors will not be included 
as comparators because the first agent in the class, canagliflozin, was 
not approved until March 2013.  As such most SGLT2 inhibitors will 
be available for less than half the study period and the sample that will 
accumulate will most likely insufficient for powered analysis.
Patients with prior use of a medication within the same class will be 
excluded from the primary analysis.  We will also conduct a secondary 
analysis including DPP4 initiators with or without prior use of another 
DPP4, pioglitazone users with or without prior rosiglitazone use, and 
2nd generation sulfonylurea use with or without prior sulfonylurea use.
Study design:
Observational cohort study
Population:
Patients ≥18 years old with a recorded diagnosis of type 2 diabetes 
mellitus (T2DM) who initiated linagliptin, sitagliptin, saxagliptin, 
alogliptin, glitazones, or 2nd generation sulfonylureas 
(Glipizide,Glimepiride) identified in US health insurance databases
Variables:
Pre-specified outcomes of interest include the following:

Primary outcome: Major adverse cardiovascular event
o
Coronary revascularization (elective and non-elective 
procedure)
o
Acute coronary syndrome (ACS) hospitalization
o
Stroke (Ischemic and hemorrhagic stroke)

Individual components of the composite major adverse 
cardiovascular event listed above
Secondary outcomes:

Heart failure hospitalization 

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
Incident End-Stage Renal Disease (ESRD) 

Acute renal failure (ARF)

ARF that requires dialysis
Data sources:
Two United States commercial health insurance databases:
UnitedHealth 2006 through June 2013 and
Marketscan 2006 through June 2013 
both with 6-month updates through Dec 2016
Data include claims for prescriptions, inpatient and outpatient visits 
and procedures, and insurance plan enrollment information and 
demographics.  Lab test results are available for a subset of the 
population.
Study size:
~ 30,000 linagliptin initiators, with other DPP-4, 2nd generation of 
SUs, Glitazones of ~30,000 each of the comparator groups
Data analysis:
For each comparison, study cohorts will be formed by propensity score 
matching within blocks of calendar time.
This study will compare rates of outcomes among patients who initiate 
Linagliptin versus initiators of other DPP-4s, 2nd generation of SUs, 
glitazones. 
 
 
Analyses will account for different follow-up times and censoring.  
 
A total of seven interim analyses will be conducted starting from Jun 
2014.
The final analyses will be based on data from May 2011- Dec 2016 
Patient characteristics will be based on all available information up to 
January 2006.

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Milestones:
Year 1
Dec, 2012    Contract
Apr, 2013    Draft Protocol
Jun, 2014   Final Protocol
Year 2
Oct, 2014    Interim Report
Jan, 2015   Interim Report
Year 3
Jun, 2015    Interim Report
Dec, 2015   Interim Report
Year 4 
Jun, 2016    Interim Report
Dec, 2016   Interim Report
Year 5
Jun, 2017   Interim Report
Year 6
Feb, 2018   Draft Final Report
Apr, 2018   Final Report

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4.
AMENDMENTS AND UPDATES
None.

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5.
MILESTONES
Milestone
Planned Date
Registration in the EU PAS 
register
30 June 2014
Start of data collection
1 July 2014
End of data collection
31 January 2018
Interim report 1
31 Oct2014
Interim report 2
31 January 2015
Interim report 3
30 June 2015
Interim report 4
31 December 2015
Interim report 5
30 June 2016
Interim report 6
31 December 2016
Interim report 7
30 June 2017
Draft final report
28 February 2018
Final report of study results:
31 April 2018
Planned dates for the following milestones:
Date
Phase 4
Data Source
Milestone
Month
United
Claims and lab data are released 
every 6 months in Jan and Jul 
(6-month lag time)
MarketScan
Claims data are released quarterly
in Mar, Jun, Sept, and Dec 
(9-month lag time) 
Lab data are released yearly 
in Dec (12-month lag time)  
Year 1
Dec, 2012
Contract
0
Apr, 2013
Draft Protocol
4
June, 2014
Final Protocol
18
Year 2
Oct, 2014
Interim Report
22
Data through Jun 2013
(Update received in Jan 2014)
Claims through Jun 2013
(Update received in Mar 2014)
Labs through Dec 2012
(Update received in Dec 2013)

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Jan, 2015
Interim Report
25
Data through Dec 2013
(Update received in Jul 2014)
Claims through Dec 2013 
(Update received in Sept 2014)
Labs through Dec 2012
(Update received in Dec 2013)
Year 3
Jun, 2015
Interim Report
30
Data through Jun 2014
(Update received in Jan 2015)
Claims through Jun 2014
(Update received in Mar 2015)
Labs through Dec 2013
(Update received in Dec 2014)
Dec, 2015
Interim Report
36
Data through Dec 2014
(Update received in Jul 2015)
Claims through Dec 2014
(Update received in Sept 2015)
Labs through Dec 2013
(Update received in Dec 2014)
Year 4
Jun, 2016
Interim Report
42
Data through Jun 2015
(Update received in Jan 2016)
Claims through Jun 2015
(Update received in Mar 2016)
Labs through Dec 2014
(Update received in Dec 2015)
Dec, 2016
Interim Report
48
Data through Dec 2015
(Update received in Jul 2016)
Claims through Dec 2015
(Update received in Sept 2016)
Labs through Dec 2014
(Update received in Dec 2015)
Year 5
Jun, 2017
Interim Report
54
Data through Jun 2016
(Update received in Jan 2017)
Claims through Jun 2016
(Update received in Mar 2017)
Labs through Dec 2015
(Update received in Dec 2016)
Year 6
Feb, 2018
Draft Final 
Report
62
Data through Dec 2016
(Update received in Jul 2017)
Claims through Dec 2016
(Update received in Dec 2017)
Labs through Dec 2016
(Update received in Dec 2017)
Apr, 2018
Final Report
64
Data through Dec 2016
(Update received in Jul 2017)

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6.
RATIONALE AND BACKGROUND
Dipeptidyl peptidase-4 (DPP-4) inhibitors, including linagliptin, saxagliptin, alogliptin and 
sitagliptin, are a new class of oral hypoglycemic agents approved in the United States. They are 
indicated for use as an adjunct to diet and exercise to improve glycemic control in adults with 
type 2 diabetes mellitus (T2DM). Evidence to date suggests that these drugs offer advantages 
over older therapies in that they are weight-neutral, are associated with a minimal risk of 
hypoglycemia, and can be administered with once-daily dosing.[P12-05315]  Linagliptin offers 
a further advantage in that its dose does not need to be adjusted based on renal or hepatic 
function.[P12-05992]  While there do not appear to be contraindications (except for 
hypersensitivity to the active ingredient or any of the excipients) to the use of Linagliptin, the 
long-term safety and effectivness have not been well characterized. 
Given the high prevalence of T2DM, it is important to understand the comparative safety and 
effectiveness of oral hypoglycemic agents. 
This protocol is for a series of comparative effectiveness and safety analyses within 
periodically updated cohorts of patients initiating linagliptin, other DPP-4 inhibitors, and other 
oral hypoglycemic medications, followed longitudinally for the occurrence of a variety of 
health outcomes. The initial analyses will be based on data from May 2011 through June 
2013and will be sequentially updated every 6 months through December 2016.
Table 1
Cohort-defining non-insulin hypoglycemic medications 
Class
Drug
FDA approval 
date
Combination products
Dipeptidyl 
peptidase-4 
(DPP-4) 
inhibitors
Linagliptin
May 2, 2011
+ metformin (Jentadueto).   approved Jan 30, 2012
Sitagliptin
Oct 16, 2006
+ metformin (Janumet, Janumet XR), 
+ simvastatin (Juvisync),
Saxagliptin
July 31, 2009
+ metformin (Kombiglyze XR)
Alogliptin
Jan 25, 2013
+ metformin (Kazano)
+ pioglitazone (Oseni)
Glitazones
Pioglitazone
Jul 15, 1999
+ metformin (ACTOplus met, ACTOplus met XR)
+ glimepiride (Duetact)
2nd Generation 
Sulfonylureas
Glipizide
May 8, 1984
+ metformin
Glimepiride
Nov 30, 1995
+ rosiglitazone (Avandaryl)
+ pioglitazone (Duetact)
Glyburide
May 1, 1984
+ metformin (Glucovance, generic)

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7.
RESEARCH QUESTION AND OBJECTIVES
This protocol is for a series of comparative effectiveness and safety analyses within 
periodically updated cohorts. The specific objectives of this surveillance program are: 

To conduct a multi-year research program that establishes and periodically updates 
initiator cohorts of linagliptin, within-class comparators (saxagliptin, sitagliptin, 
alogliptin), and out-of-class comparators (glitazones or second generation of SUs), 
describes patient characteristics over time, and longitudinally follows drug initiators for 
the incidence of a variety of health outcomes (i.e. cardiovascular outcomes, 
 renal impairment 
).

To conduct direct comparisons among hypoglycemic agents and quantify the 
association between hypoglycemic choice and the occurrence of both specific outcomes 
of interest and other outcomes potentially brought forward during the study period.
The primary outcomes of interest will be the occurrence of a major cardiovascular event (defined as 
composite of coronary revascularization, acute coronary syndrome hospitalization, ischemic and 
hemorrhagic stroke) and the individual components of the composite cardiovascular outcome. Heart 
failure hospitalization, incident end-stage renal disease and acute renal failure will be considered 
secondary outcomes of interest.  There are no a priori hypotheses.

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8.
RESEARCH METHODS
Description of the research methods, including:
8.1
STUDY DESIGN
This study will involve a sequential new user cohort design (of Linagliptin and the other 
comparators). 
This study design will allow the inclusion of additional subjects and follow-up time, as data 
become available, over the course of the study period. 
8.2
SETTING
Initiators of linagliptin and other oral hypoglycemic medications from UnitedHealth Research 
Database and MarketScan source data between May 2011 and Jun 2013, with 6-month updates 
through December 2016.  
The United Healthcare and Marketscan data were selected as data sources for several reasons.  
These commercial databases involve relatively short lag-times for inclusion of data so that they 
are more up-to-date than many alternatives (e.g. Medicare data) and they provide a fairly 
complete picture of interactions between patients and the healthcare system for a large cohort 
of patients.  Further, there is the opportunity to go beyond the source data through linkages to 
laboratory data and electronic medical records. 
Finally, the inclusion of two data sources will increase the size of the elderly population 
available for the study, since many patients over the age of 65 transition from commercial 
health insurers to Medicare and are thereby under-represented in commercial databases.
8.2.1
Subjects
From the UnitedHealth Research Database and MarketScan source data, we will identify 
patients with a recorded diagnosis of type 2 diabetes mellitus (T2DM) who initiated linagliptin, 
sitagliptin, saxagliptin, alogliptin, pioglitazone, or 2nd generation sulfonylureas between May 
2011 and June 2013. The following inclusion and exclusion criteria were developed with the 
goal of obtaining a population that is broadly representative of patients with T2DM and within 
which valid comparisons can be made due to the selection of linagliptin users and users of other 
oral glucose medications that are used at similar stages of diabetes.
Inclusion criteria:

Patients ≥18 years old

Patients received a dispensing of linagliptin or a comparator hypoglycemic (see table 1) 
medication within the study timeframe AND had a diagnosis of T2DM (ICD-9 Dx code 
of 250.x0 or 250.x2) prior to drug initiation.1
We are restricting to initiators with evidence of type T2DM in order to exclude 
1 All available data prior to and including the index date will be used to identify the presence of a recorded T2DM 
and T1DM diagnoses

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patients receiving non-insulin hypoglycemic agents for other indications (e.g., 
polycystic ovary syndrome, infertility, weight loss, etc.).

The first dispensing is preceded by at least 6 months of continuous enrollment in the 
study database, defined as the routine maximum allowed bridge for administrative gaps 
of enrollment, i.e, <32 days enrollment gap using the enrollment and disenrollment 
dates.
‘New users’ definition:  The study will focus on “new users”, defined as patients with no 
dispensing of that particular medication in the prior 6 months. The patients will be additionally 
classified in:

“Treatment-naive new users”, defined as patients with no use of any hypoglycemic 
agent (including insulin) in the prior 6 months,

“non-naive new users”, defined as patients initiating a new hypoglycemic agent as a
switch from or addition to a previous hypoglycemic medication, will also be 
identified and investigated in secondary analyses. 
All patients initiating hypoglycemic drugs will be classified as initiators of a specific 
hypoglycemic drug or class on the basis of the first in time drug initiation within a time-block. 
Patients’ follow-up will terminate at the end of their exposure time window, which will vary 
according to the specific outcome and analysis as specified in section 8.3. If the same patient 
re-initiates treatment later on, (s)he may re-enter the cohort at that time, but only in the case 
that the patient was not successfully matched during the time-block corresponding to his/her 
original drug initiation and meets all inclusion criteria at the time of the matching. Thus, 
patients will contribute only once to the balanced study cohort (Figure 1).  Patients with prior 
within-class medication use during the preceding 6 months will be excluded from the primary 
analyses.
Exclusion criteria: 

Patients with missing or ambiguous age or sex information.

Patients under the age of 18

Patients with type 1 diabetes mellitus (T1DM) defined as at least 1 inpatient or 
outpatient ICD-9 Dx code of 250.x1 or 250.x3 prior to drug initiation1. Although the 
use of oral hypoglycemic drugs is a strong predictor for underlying T2DM [R12-3697], 
it was also decided to exclude the patients with prior recorded diagnosis of T1DM to 
further limit the chances of misclassification of the underlying disease.

Secondary diabetes, and gestational diabetes in the 6 months prior to drug initiation 

History of cancer at any time prior to drug initiation 

End-stage renal disease (ESRD) in the 6 months prior to drug initiation 

HIV diagnosis or treatment at any time prior to drug initiation

Organ transplant at any time prior to drug initiation

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Table 2
Exclusion criteria: Definition of secondary diabetes, cancer history, 
ESRD, HIV, and organ transplant
Secondary diabetes
ICD-9 procedure:
249.xx  Secondary diabetes
648.8x  Gestational diabetes
History of cancer
MALIGNANT NEOPLASMS                                  140.xx-208.xx (except 173.xx, non-melanoma 
skin cancer)
NEUROENDOCRINE TUMORS                             209.xx
BENIGN NEOPLASMS                                            210-229.xx 
CARCINOMA IN SITU                                            230-234.xx
NEOPLASMS OF UNCERTAIN BEHAVIOR        235-238.xx
NEOPLASMS OF UNSPECIFIED NATURE          239.xx
ESRD
A laboratory measurement of eGFR < 15ml/min/1.73m2
OR
DIALYSIS
ICD-9 procedure:
39.95 hemodialysis
54.98 peritoneal dialysis
38.95 Venous catheterization for renal dialysis
39.27 Arteriovenostomy for renal dialysis
39.42 Revision of arteriovenous shunt for renal dialysis
39.43 Removal of arteriovenous shunt for renal dialysis
ICD-9 diagnoses:
V45.1 renal dialysis status
V56.0 extracorporeal dialysis
V56.8 peritoneal dialysis
CPT4:
90935
HEMODIALYSIS PROC W/SINGLE PHYSICIAN EVALUATION
90937
HEMODIALYSIS, REPEATED EVAL, W/WO REVISION DIALYSIS
PRESCRIPTION
90940
HEMODIALYSIS ACCESS FLOW STUDY, BY INDICATOR DILUTION METHOD,
HOOK UP;  MEASUREMENT & DISCONNECTION
90945
DIALYSIS, OTHER THAN HEMODIALYSIS, SINGLE PHYSICIAN EVAL
90947
DIALYSIS PROCEDURE, OTHER THAN HEMODIALYSIS, REPEATED
PHYSICIAN EVAL
90989
DIALYSIS TRAINING, PATIENT, W/HELPER WHERE APPLICABLE, ANY MODE,
COMPLETED COURSE
90993
DIALYSIS TRAINING, PATIENT, W/HELPER WHERE APPLICABLE, ANY 
MODE, COURSE INCOMPLETE, PER SESSION
99512
HOME VISIT, HEMODIALYSIS
99559
HOME INFUSION, PERITONEAL DIALYSIS, PER VISIT
OR
RENAL TRANSPLANT
V42.0    Kidney transplant
55.6x     Kidney transplant
996.81  Complication of transplanted kidney
CPT4:
50360
RENAL ALLOTRANSPLANTATION, IMPLANTATION, GRAFT; W/O DONOR 
& RECIPIENT NEPHRECTOMY
50365
RENAL ALLOTRANSPLANTATION, IMPLANTATION, GRAFT; W/RECIPIENT 
NEPHRECTOMY
50380
RENAL AUTOTRANSPLANTATION, REIMPLANTATION, KIDNEY
OR
RENAL ICD9-defined ESRD
585.5 ESKD with no mention of dialysis
585.6 ESKD on dialysis

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Table 2 (cont’d)
Exclusion criteria: Definition of secondary diabetes, cancer history, 
ESRD, HIV, and organ transplant
HIV
042 Human immunodeficiency virus [HIV] disease
079.53 Human immunodeficiency virus, type 2 [HIV-2]
V08 Asymptomatic human immunodeficiency virus [HIV] infection status
OR filled prescription for HIV treatment:
Abacavir 
Amprenavir 
Atazanavir 
Darunavir 
Delavirdine 
Didanosine
Efavirenz 
Emtricitabine 
Enfuvirtide 
Etravirine 
Fosamprenavir 
Indinavir 
Lamivudine-Zidovudine
Maraviroc 
Nelfinavir 
Nevirapine 
Raltegravir 
Rilpivirine 
Ritonavir 
Ritonavir-Lopinavir
Saquinavir 
Stavudine 
Tipranavir 
Zalcitabine 
Zidovudine
Organ Transplant
ICD-9 diagnoses:
V42.0 Kidney
V42.1 Heart
V42.6 Lung
V42.7 Liver
V42.8x Other specified organ or tissue
V42.81 Bone marrow
V42.83 Pancreas
V42.84 Intestines
V42.89 Other
V42.9x Unspecified organ or tissue
V58.44 Aftercare following organ transplant
E878.0x Surgical operation with transplant of whole organ
996.8x Complications of transplanted organ
ICD-9 procedures:
33.5x Lung transplant
33.6x Combined heart-lung transplantation
37.51 Heart transplantation
41.0x Bone marrow 
46.97 Transplant of intestine
50.5x Liver transplant
52.8x Transplant of pancreas
55.6x Transplant of kidney

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Table 2 (cont’d)
Exclusion criteria: Definition of secondary diabetes, cancer history, 
ESRD, HIV, and organ transplant
CPT4 codes
32851
LUNG TRANSPLANT, SINGLE; W/O CARDIOPULMONARY BYPASS
32852
LUNG TRANSPLANT, SINGLE; W/CARDIOPULMONARY BYPASS
32853
LUNG TRANSPLANT, DOUBLE (BILAT SEQUENTIAL/EN BLOC); W/O 
CARDIOPULMONARY BYPASS
32854
LUNG TRANSPLANT, DOUBLE (BILAT SEQUENTIAL/EN BLOC); 
W/CARDIOPULMONARY BYPASS
33935
HEART-LUNG TRANSPLANT W/RECIPIENT CARDIECTOMY-
PNEUMONECTOMY
33945
HEART TRANSPLANT, W/WO RECIPIENT CARDIECTOMY
38240
BONE MARROW/BLOOD-DERIVED PERIPHERAL STEM CELL 
TRANSPLANTATION; ALLOGENIC
38241
BONE MARROW/BLOOD-DERIVED PERIPHERAL STEM CELL 
TRANSPLANTATION; AUTOLOGOUS
44135
INTESTINAL ALLOTRANSPLANTATION; FROM CADAVER DONOR
44136
INTESTINAL ALLOTRANSPLANTATION; FROM LIVING DONOR
47135
LIVER ALLOTRANSPLANTATION; ORTHOTOPIC, PARTIAL/WHOLE, FROM 
CADAVER/LIVING DONOR, ANY AGE
47136
LIVER ALLOTRANSPLANTATION; HETEROTOPIC, PARTIAL/WHOLE, FROM 
CADAVER/LIVING DONOR, ANY AGE
48554
TRANSPLANTATION, PANCREATIC ALLOGRAFT
48556
REMOVAL, TRANSPLANTED PANCREATIC ALLOGRAFT
50360
RENAL ALLOTRANSPLANTATION, IMPLANTATION, GRAFT; W/O DONOR & 
RECIPIENT NEPHRECTOMY
50365
RENAL ALLOTRANSPLANTATION, IMPLANTATION, GRAFT; W/RECIPIENT 
NEPHRECTOMY
50370
REMOVAL, TRANSPLANTED RENAL ALLOGRAFT
50380
RENAL AUTOTRANSPLANTATION, REIMPLANTATION, KIDNEY
8.2.2
Cohort formation
We will receive new data as they become available on a periodic basis (every 6 months) and we 
will update the study cohorts through Dec 2016. Initiators of linagliptin, and comparator drugs 
identified in each data cut, as previously described, will form sequential cohorts.  
In each sequential cohort we will balance baseline covariates among patients initiating each 
drug by means of a multivariate confounder summary score (by matching on the exposure 
propensity score). In the primary as-treated analysis, patients’ follow-up will end at treatment 
discontinuation, allowing a grace period, as specified in table 4. If the same patient re-initiates 
treatment later on after a treatment gap of ≥6 months, (s)he may re-enter the cohort at that time, 
but only in case the patient was not successfully matched during the time-block corresponding 
to his/her original drug initiation (Figure 1).

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Figure 1
Patient
8.3
VARIABLES
8.3.1
Exposure

The primary contrast o
users” of 2nd generation
defined as patients with
months.  The primary a
medication in the same

In secondary analyses 
other agents among “tr
hypoglycemic agent (in
users”, defined as patie
addition to a previous h
specific drug comparat
comparison, but is perm
treatment initiation (Ta
of a medication in the s
Concomitant initiation or prev
defining medications (i.e. hypo
the day of linagliptin or compa
used for balancing or stratifica
tudies based on existing data
© 2014 Boehringer Ingelheim International GmbH or one or more o
t Selection Flow Chart for initial time-block
of interest is between “new users” of linaglipt
n of SU, pioglitazone, other DPP-4 inhibitors
h no dispensing of that particular medication 
analysis will be further restricted to patients w
e class during the prior 6 months.
the initiation of linagliptin will be compared 
reatment-naive new users”, defined as patient
ncluding insulin) in the prior 6 months, and “
ents initiating a new hypoglycemic agent as a
hypoglycemic medication. Patients filling lin
tor on the same date will not be considered fo
mitted for other comparisons.
able 3).  These analyses will be restricted to p
same class during the prior 6 months.
valent use of hypoglycemic medications that a
oglycemic medications either initiated or con
arator initiation) will be accounted for in the 
ation. This includes medications that are initia
Page 24 of 96
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of its affiliated companies
in and similar “new 
s, with new use 
in the prior 6 
with no use of a 
with the initiation of 
ts with no use of any 
“non-naive new 
a switch from or 
nagliptin and each 
or that particular 
 
patients with no use 
are not cohort-
ntinuously used on 
study analyses and 
ated as part of a 

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fixed-dose combination.  A list of not cohort-defining hypoglycemic medications is provided in 
Annex 3 and will be updated over time as additional agents are approved. 
Similarly, past therapy with hypoglycemic agents that are not cohort-defining medications 
(defined as any use in the 6-month period prior to linagliptin or comparator initiation with no 
prevalent use on the day of initiation of linagliptin or comparator) will be accounted for in the 
study analyses involving non-naive new users and used for balancing or stratification.  
Operational definitions for study comparisons of interest and planned analyses are outlined in 
Table 3
Table 3
Study comparisons of interest and planned analyses
Comparison
Exposure
Comparator
Analyses1
Primary 
comparisons
1
Linagliptin
Other DPP4 inhibitors 
(Saxagliptin or Sitagliptin
or Alogliptin)
Overall
By subgroups based on the status 
of treatment naive/non-naive new 
user 
By subgroups based on the 
presence2 or non-presence of :
Metformin
Insulin
2
Linagliptin
Pioglitazone
3
Linagliptin
2nd Generation 
Sulfonylureas
Secondary 
comparisons
4
Linagliptin 
monotherapy3
Comparator monotherapy5
Overall
5
Linagliptin 
+ metformin
(Dual therapy4)
Comparator5
+ metformin
(Dual therapy)
Overall
6
Linagliptin, 
allowing prior use 
of another DPP4
Comparator5, allowing prior 
use of another within-class 
agent
Overall
1All the analyses will be balanced on the basis of past or concomitant use of other hypoglycemic medications (i.e., 
metformin, insulin, sulfonylureas, glitazones, GLP-1 receptor agonists, other DPP4 inhibitors, meglitinides, alpha-
glucosidase inhibitors, SGLT2 inhibitors) through propensity score matching.
2Presence of metformin or insulin is defined as either past or concomitant therapy with these agents.
3 Monotherapy is defined as no concomitant initiation or prevalent use of other hypoglycemic agents on the day of 
linagliptin or comparator initiation. 
4 Dual therapy is defined as concomitant initiation or prevalent use of metformin on the day of linagliptin or comparator 
initiation, and no concomitant initiation or prevalent use of other hypoglycemic agents.
5 Linagliptin will be compared to each comparator (DPP4 inhibitors, pioglitazone, and 2nd generation sulfonylureas)
separately.
We specify multiple comparators because there are multiple treatment alternatives to linagliptin 
for patients with T2DM. 
Within-class comparators, i.e. other DPP-4 inhibitors. Although linagliptin is the only DPP-4 
inhibitor that does not require dose adjustment for severe renal impairment, other DPP-4 

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inhibitors are expected to have utilization patterns more similar to linagliptin than out of class 
comparators and to be prescribed to patients with similar clinical profiles.
Out-of-class comparators, i.e. second-generation sulfonylureas and pioglitazone, will be 
considered in order to investigate between-class effects. 2nd generation sulfonylureas and 
thiazolidinediones are oral hypoglycemics and are not usually used as first-line therapy, so that 
they represent more similarly-used alternatives to linagliptin than other treatment options such 
as glucagon-like peptide-1 (GLP-1) receptor agonists or metformin.  SGLT2 inhibitors will not be 
included as comparators because the first agent in the class, canagliflozin, was not approved until March 
2013.  As such most SGLT2 inhibitors will be available for less than half the study period and the 
sample that will accumulate will most likely be insufficient for powered analysis.
Study follow-up
The primary analyses will use an “as treated” approach (AT). Because of the considerable 
difference in the underlying biology of the outcomes considered in this research program, 
different definitions for the exposure risk window [R13-1120] will be explored for each 
outcome (Table 4). Separately for each outcome, follow-up will start the day after the initiation 
of linagliptin or a comparator and will end at one of the following (whichever comes first):

Drug discontinuation (date of last dispensing + days supply + grace period). The grace 
period is a time period after exposure end during which observed outcomes are still 
attributed to the exposure. Grace period will vary according to the specific outcome.

Drug augmentation or switching to a comparator 

A study outcome

End of continuous enrollment, i.e. an enrollment gap of ≥32 days

Death from any cause

End of the observation period. According to the specific outcome, the observation 
period may use all the available data or end at a pre-specified date.
 switching of exposure is handled by the AT approach.  
 
 
To account for switching of exposure we will use a modified AT approach, with a latency 
period of 90 days.  To address potential cumulative dose effects, we will conduct further 
analyses that stratify the AT and ITT analyses for duration of follow-up.  Strata will be 
determined empirically, using 6 months blocks if feasible.

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Table 4
Variations in exposure risk window definitions – AT approach
Outcome
Follow-up 
initiation
Follow-up 
initiation 
when a lag 
period is 
considered
Observation period
Grace period1
(Main 
analyses)
Grace 
period 
(Sensitivit
y 
analyses)
Myocardial 
Infarction
Day 1
Day 31
Follow-up uses all the 
available data 
90 days
30 days
Major 
cardiovascular 
event
Day 1
Day 31
Follow-up uses all the 
available data 
90 days
30 days
Renal 
impairment
Day 1 
Day 31
Follow-up uses all the 
available data
90 days
30 days
1 The grace period is a time period after exposure end during which observed outcomes are still attributed to the exposure.
Secondary analyses will use an “intention-to-treat” (ITT) approach (first exposure carried 
forward). Separately for each outcome, follow-up will start the day after the initiation of 
linagliptin or a comparator and will end at one of the following (whichever comes first):

A study outcome

End of continuous enrollment

Death from any cause

End of the observation period. According to the specific outcome, the observation 
period may use all the available data or end at a pre-specified date.
Similarly to the AT approach, different definitions of the exposure risk window will be 
explored in the ITT analyses for each outcome (Table 5).

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Table 5
Variations in exposure risk window definitions – ITT approach
Outcome
Follow-up 
initiation
Follow-up initiation 
when a lag period is 
considered
Observation period
Myocardial 
infarction
Day 1
Day 31
Follow-up uses all available data 
Major 
cardiovascular 
event
Day 1
Day 31
Follow-up uses all available data 
Renal impairment
Day 1 
Day 31 
Follow-up uses all available data 
8.3.2
Outcomes
Pre-specified outcomes of interest include: 
Primary outcome:

Major adverse cardiovascular event as a composite of:

Coronary revascularization (elective and non-elective procedure)

Acute coronary syndrome (ACS) hospitalization (including acute MI)

Stroke (Ischemic and hemorrhagic stroke)

Individual components of the composite major adverse cardiovascular event listed 
above (ischemic and hemorrhagic stroke, acute MI will be assessed separately)
Secondary outcomes:

Heart failure hospitalization 

Incident End-Stage Renal Disease (ESRD) 

Acute renal failure (ARF)

ARF that requires dialysis

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Further outcomes: 

Any incident malignant neoplasms

Site-specific incident malignant neoplasms grouped into categories used by the 
Surveillance, Epidemiology and End Results (SEER) program

Glomerular Filtration Rate (GFR) event, among patients with laboratory test results

Acute Pancreatitis

Severe skin reactions 
o
Erythema multiforme, Stevens-Johnson syndrome, or Toxic epidermal 
necrolysis 
o
Bullous pemphigoid

All cause mortality
Components of the pre-specified outcomes (e.g. coronary revascularization, ACS 
hospitalization) will be considered as “further outcomes.”
Table 6
Outcome definitions
Outcome
Code(s)
Comments
Coronary 
revascularization
procedure for revascularization (PTCA, stenting, CABG 
surgery):
PTCA:
Inpatient CPT-4: 92973, 92982, 92984, 92995, 92996, 92920 
– 92921, 92924 – 92925, 92937, 92938, 92941, 92943, 92944
OR –
Inpatient ICD-9 procedure: 00.66, 36.01, 36.02, 36.03, 36.05, 
36.09
[P10-01452]

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Table 6 (cont’d)
Outcome definitions
Outcome
Code(s)
Comments
Stenting:
Inpatient CPT-4:  92980, 92981, 92928 – 92929, 92933 -
92934
OR –
Inpatient ICD-9 procedure: 36.06, 36.07
CABG:
Inpatient CPT-4: 33510 – 33536, 33545, 33572
       OR –
Inpatient ICD-9 procedure: 36.1x, 36.2x
Transmyocardial revascularization:
Inpatient CPT-4: 33140, 33141
       OR -
Inpatient ICD-9 procedure: 36.31-36.34
Myocardial infarction 
(MI)
Inpatient ICD-9 diagnosis: 
410.X (acute myocardial infarction) excluding 410.x2,  as the 
principal (primary) or the next (secondary) diagnosis
PPV 94% in Medicare  
claims data [R11-
4316]
PPV 88.4% in 
commercially-insured 
population [R11-4887]
Acute coronary 
syndrome (ACS)
Acute myocardial infarction
Inpatient ICD-9 diagnosis: 
410.X (acute myocardial infarction) excluding 410.x2,  as the 
principal (primary) or the next (secondary) diagnosis
OR
Intermediate coronary syndrome and other acute and subacute 
forms of ischemic heart disease
Inpatient ICD-9 diagnosis:
411.xx as primary or secondary
[P10-01452]
Ischemic stroke
Inpatient ICD-9 diagnosis:
433.x1, 434.x1 (pre-cerebral/cerebral artery occlusion)
PPV 95.5% in 
commercially-insured 
population [R11-4887]
Hemorrhagic stroke
Inpatient ICD-9 diagnosis:
430.x (SAH) or 431.x (ICH)
(both as primary discharge diagnoses)
PPV 89% (80% if all 
discharge diagnoses) 
for ICH;
PPV 94% (86% if all 
discharge diagnoses) 
for SAH [R13-4101]
Hospitalization with 
heart failure (HF)
Inpatient ICD-9 diagnosis (primary diagnosis): 
428.x, 398.91, 402.01, 402.11, 402.91, 404.01, 404.11, 
404.91, 404.03, 404.13, 404.93
Identification of 
current HF: 
Inpatient ICD-9 
diagnosis (1st position):
Sensitivity 33% 
Specificity 99%
in Medicare claims 
data [R11-4334]

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Table 6 (cont’d)
Outcome definitions
Outcome
Code(s)
Comments
ESRD
eGFR < 15 ml/min/1.73m2
OR
Dialysis
Inpatient or outpatient ICD-9 procedure:
39.95 hemodialysis
54.98 peritoneal dialysis
Inpatient or outpatient ICD-9 diagnosis:
V45.1 renal dialysis status
V56.0 extracorporeal dialysis
V56.1 Fitting and adjustment of extracorporeal dialysis 
catheter (Waikar)
V56.2 Fitting and adjustment of peritoneal dialysis catheter 
(Waikar)
V56.31 Encounter for adequacy testing for hemodialysis 
(Waikar)
V56.32 Encounter for adequacy testing for peritoneal dialysis 
(Waikar)
V56.8 peritoneal dialysis
585.6 ESKD on dialysis
Inpatient or outpatient CPT4:
90935 HEMODIALYSIS PROC W/SINGLE PHYSICIAN
EVALUATION
90937 HEMODIALYSIS, REPEATED EVAL, W/WO
REVISION DIALYSIS PRESCRIPTION
90940 HEMODIALYSIS ACCESS FLOW STUDY, BY
INDICATOR DILUTION METHOD, HOOK UP;  
MEASUREMENT & DISCONNECTION
90945 DIALYSIS, OTHER THAN HEMODIALYSIS,
SINGLE PHYSICIAN EVAL
90947 DIALYSIS PROCEDURE, OTHER THAN
HEMODIALYSIS, REPEATED PHYSICIAN EVAL
90989 DIALYSIS TRAINING, PATIENT, W/HELPER
WHERE APPLICABLE, ANY MODE, COMPLETED
COURSE
90993 DIALYSIS TRAINING, PATIENT, W/HELPER 
WHERE APPLICABLE, ANY MODE, COURSE 
INCOMPLETE, PER SESSION
99512 HOME VISIT, HEMODIALYSIS
99559 HOME INFUSION, PERITONEAL DIALYSIS, PER
VISIT
OR 
Renal transplant
Inpatient or outpatient ICD-9 diagnosis:
V42.0 Kidney transplant
55.6x  Kidney transplant
Inpatient or outpatient CPT4:
50360 RENAL ALLOTRANSPLANTATION, 
IMPLANTATION, GRAFT; W/O DONOR & 
RECIPIENT NEPHRECTOMY
50365 RENAL ALLOTRANSPLANTATION, 
[R12-3640]
Table 6 (cont’d)
Outcome definitions
Outcome
Code(s)
Comments

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Outcome
Code(s)
Comments
IMPLANTATION, GRAFT; W/RECIPIENT 
NEPHRECTOMY
50380 RENAL AUTOTRANSPLANTATION, 
REIMPLANTATION, KIDNEY
Acute renal failure 
(ARF)
Inpatient ICD-9 diagnosis:
584.5x ARF with lesion of tubular necrosis
584.6x ARF with lesion of renal cortical necrosis
584.7x ARF with lesion of renal medullary [papillary] 
necrosis
584.8x ARF with other specified pathological lesion in kidney
584.9x ARF, unspecified 
Sensitivity 35%
Specificity 98%
PPV 48% 
NPV 96% [R14-1495]
Acute renal failure 
that requires dialysis 
(ARF-D)
Inpatient ICD-9 diagnosis:
584.5x ARF with lesion of tubular necrosis
584.6x ARF with lesion of renal cortical necrosis
584.7x ARF with lesion of renal medullary [papillary] 
necrosis
584.8x ARF with other specified pathological lesion in kidney
584.9x ARF, unspecified
AND any of the following inpatient codes :
39.95 hemodialysis
V45.1 renal dialysis status
V56.0 extracorporeal dialysis
V56.1 fitting and adjustment of dialysis catheter
Sensitivity 90%
Specificity 94%
PPV 94%
NPV 90% [R14-1495]
GFR event
Persistent 25% decrease in GFR (~30 ml/min/1.73m2) 
[R12-3640]
All malignant 
neoplasms 
Inpatient or outpatient ICD-9 diagnosis:
140.xx-172.xx, 174.xx-208.xx
[R14-1517]

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Table 6 (cont’d)
Outcome definitions
Outcome
Code(s)
Comments
Specific malignant 
neoplasms

Breast

Urinary Bladder

Pancreas 

Oral and Pharynx 

Esophagus 

Stomach 

Colon & Rectum 
o
Colon 
o
Rectum 

Liver 

Larynx 

Lung & Bronchus 

Cervix Uteri 

Corpus Uteri 

Ovary 

Prostate 

Testis 

Kidney & Renal 
Pelvis 

Brain 

Thyroid 

Hodgkin 
Lymphoma 

Non-Hodgkin 
Lymphoma 

Myeloma 

All Leukemia 
o
Acute 
Lymphatic 
o
Chronic 
Lymphatic 
o
Acute 
Myeloid 
o
Chronic 
Myeloid 

Melanoma 
Inpatient or outpatient ICD-9 diagnosis:

174.xx-175.xx

188.xx

157.xx

140.xx -149.xx

150.xx

151.xx

153.xx -154.xx
o
153.xx
o
154.xx

155.xx

161.xx

162.xx -163.xx

180.xx

182.xx

183.xx

185.xx

186.xx

189.xx

191.xx

193.xx

201.xx

200.xx

203.xx

204.xx -208.xx
o
204.xx
o
204.1x
o
205.xx
o
205.1x

172.xx
[R14-1517]
Acute Pancreatitis
Inpatient ICD-9 diagnosis:
577.0x (as primary diagnosis) 
Sensitivity 93%
Specificity 72% [R14-
1516] [R14-1501]

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Table 6 (cont’d)
Outcome definitions
Outcome
Code(s)
Comments
Erythema multiforme 
OR Stevens-Johnson 
syndrome OR Toxic 
epidermal necrolysis 
Inpatient ICD-9 diagnosis:
695.10 Erythema multiforme, unspecified Erythema iris
Herpes iris
695.11 Erythema multiforme minor
695.12 Erythema multiforme major
695.13 Stevens-Johnson syndrome
695.14  SJS-TEN overlap syndrome
695.15 Toxic epidermal necrolysis, Lyell’s syndrome
  695.19 Other erythema multiforme
PPV 53-60% [R14-
1494]
Bullous pemphigoid
Inpatient ICD-9 diagnosis:
694.5x 
[P13-16208]
8.3.3
Covariates
Covariates describing demographics and healthcare characteristics will be assessed on the basis 
of enrollment information and claims over the 6 months (183 days) preceding (and including 
date of) dispensing. 
All available data prior to and including the index date might be used to identify selected 
covariates (e.g. history of diabetes). Unless specified otherwise, covariates are based on 1 in- or 
outpatient diagnosis in any position, since we strive for high sensitivity for covariate 
definitions.  A complete list is provided in Annex 3.
8.4
DATA SOURCES
The data source for this project will be a combination of claims data from United Healthcare, a 
large national commercial health insurer, and MarketScan, a research claims database from
commercial employer-sponsored health plans from January 2006 through June 2013, with 6-
month updates through Dec 2016. Because of a 6-month time lag before data become available, 
we will not have access to any information beyond June 2013 for the first interim report. Both 
data sources include meaningful numbers of older adults 65 years and older in Medicare 
Advantage plans, employer-sponsored plans covering seniors, and Medicare supplemental 
insurance plans, although it is important to note that elderly patients with Medicare Advantage 
might differ from the elderly patients with other types of Medicare coverage as they tend to be 
healthier and more likely to still be employed. These data sources readily allow for the 
identification of large numbers of exposed patients with a 6-month lag time from the 
occurrence of the service (medication dispensing) and availability of the claims for research.  
They are further suitable as a foundation for related projects that serve to describe additional 
features of the exposures, outcomes or covariates through sampled medical record review.  
Both data sources provide outpatient laboratory results data for about 20-30% of enrollees.  
We have obtained the following preliminary estimates from the UnitedHealth and MarketScan 
databases regarding the number of patients initiating DPP4 inhibitors (new users) and meeting 
the main study selection criteria in the period May 2011 – December 2012.

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Table 7
UnitedHealth and MarketScan databases Pilot Data, New Users1 of 
DPP-4 inhibitors with T2DM diagnosis2, in the period May 2011 –
December 2012*
DPP-4 
Inhibitors
United 
Healthcare
MarketScan
Total
Linagliptin
2,877
5,608
8,485
Saxagliptin
8,258
20,501
28,759
Sitagliptin
19,616
50,397
70,013
*Note: the following exclusion criteria, which will be applied in the final cohort definition, were not applied in obtaining these 
counts: history of cancer, end-stage renal disease, HIV, organ transplant.
8.5
STUDY SIZE
The ability of this research program to detect a given risk increase depends on the incidence of 
the outcome as well as the number of cohort entrants and duration of follow-up.  The table 
below provides estimates of the minimum relative rates that can be detected with 80% power 
for the major study outcomes under specific assumptions regarding their incidence in the 
comparator group (labeled “base rate”) and the accrual of person-time.  The base case 
incidence rates were derived from the literature.  We conservatively assumed that the number 
of patients initiating linagliptin each month during 2013 - 2016 is equal to the average monthly 
number of initiators during the last half of 2012, that these patients are matched 1:1 to 
comparator patients, and that each patient contributes 6 months of follow-up time.  Because of 
the large numbers of patients initiating comparator agents, we assumed that all linagliptin 
patients will be matched.  The calculations assume an alpha level of 0.05 and a 2-sided test and 
are based on methods by Peterson and George. [R14-1502]  For the purposes of this table, we
have not applied an alpha spending function or any other alpha-adjustment to reflect multiple 
testing. 
1New users are defined as patients with no dispensing of that particular medication in the prior 6 months.
2Initiators had recorded T2DM diagnosis prior to initiation of the index drug and no diagnosis of T1D

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Table 8
Projected minimum detectable relative rates by reporting period with a power of 80%
Interim 
report 1
Interim 
report 2
Interim 
report 3
Interim 
report 4
Interim 
report 5
Interim 
report 6
Interim 
report 7
Draft final 
report
Final 
report
Report Date
June, 
2014
Dec, 2014
June, 2015
Dec, 2015
June, 2016
Dec, 2016
Jun, 2017
Feb, 2018
Apr, 
2018
Data through
June, 
2013
Dec, 2013
June, 2014
Dec, 2014
June, 2015
Dec, 2015
Jun, 2016
Dec, 2016
Dec, 
2016
Cumulative 
person-years of 
observation
7,961
10,434
12,907
15,379
17,852
20,325
22,798
25,270
25,270
Base rate, 
per 100 
person-
years:
Minimum detectable relative rate:
Cardiovascular, 
scenario 1
0.4
1.8
1.7
1.6
1.6
1.5
1.5
1.5
1.4
1.4
Cardiovascular, 
scenario 2
3
[R04-2173] 
[R10-0459] 
[P14-05386] 
[P13-00007] 
[R13-3903] 
[R10-0519]
1.3
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
Hospitalization 
for acute MI, 
scenario 1
0.4
1.8
1.7
1.6
1.6
1.5
1.5
1.5
1.4
1.4

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Table 8 (cont’d)
Projected minimum detectable relative rates by reporting period with a power of 80%
Hospitalizatio
n for acute 
MI, scenario 2
1.5
1.4
1.3
1.3
1.3
1.3
1.2
1.2
1.2
1.2
Renal 
impairment, 
scenario 1
0.09
[R04-2173]
3.0
2.7
2.5
2.3
2.2
2.1
2.1
2.0
2.0
Renal 
impairment, 
scenario 2
0.4
[R12-3640]
1.8
1.7
1.6
1.6
1.5
1.5
1.5
1.4
1.4

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Table 8 (cont’d)
Projected minimum detectable relative rates by reporting period with a power of 80% 
Interim 
report 1
Interim 
report 2
Interim 
report 3
Interim 
report 4
Interim 
report 5
Interim 
report 6
Interim 
report 7
Draft final 
report
Final 
report
* For each major study outcome, we provide two scenarios based on lower (Scenario 1) and higher (Scenario 2) base rates as derived from available literature.  Because of the large 
numbers of patients initiating comparator agents, we assumed that all linagliptin patients will be matched.  The calculations assume an alpha level of 0.05 and a 2-sided test and are 
based on methods by Peterson and George. [R14-1502] For the purposes of this table, we have not applied an alpha spending function to reflect multiple testing

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8.6
DATA MANAGEMENT
The data will reside on a Linux-based computer cluster in Partners Healthcare’s state-of-the-
art computing facility located in a secure location in the Boston area. This facility houses 
clinical systems and electronic medical records for Partners hospitals, including Brigham and 
Women’s and Massachusetts General Hospitals.  Entry into the computer room requires 
passing through staffed building security, a successful palm scan, and then passing through 
staffed computer room security.  All entries and exits are logged.  We maintain 26 TB of 
redundant NetApp storage for maximal data integrity and high-speed data access.  We also 
maintain 96 TB of database storage on a Netezza parallel supercomputer. The computers and 
data files are only accessible via a local area network, which is overseen by Partners 
Healthcare Information Security, who applies the same standards used for the hospital’s 
electronic medical records systems to the research team’s data. All data are transmitted to 
programmers’ workstations in an encrypted state. Backups are created using 256-bit AES 
encryption, the current Department of Defense standard for data security, and are stored in a 
locked facility.
8.7
DATA ANALYSIS
The analyses will be based on data from May 2011- December 2016. 
The first data cut will include data between May 2011 and June 2013. 
We will receive new data as they become available on a periodic basis (every 6 months) and, 
at each data cut, we will update the original set of data, form sequential cohorts by propensity 
score (PS) matching within 6-month blocks of time, follow patients for each of the outcomes 
of interest in a prospective manner, and estimate measures of effect using person-time based 
analyses among patients who initiate linagliptin versus a comparator drug (Figure 2).  Thus 
each analysis will include all patients initiating medication between May 2011 and the end of 
the data cut for that analysis.

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Figure 2
Sequential matched cohort study schematic
8.7.1
Main Analysis
We will compare distributions of socio-demographic, clinical and utilization characteristics 
among initiators of different hypoglycemic agents, and describe changes over time with 
respect to these features in a way that will illustrate the potential for change in channelling 
over time. We will calculate event rates during follow-up for each of the specified outcomes 
in each exposure group of interest.
Unadjusted and adjusted relative risks (hazard ratios) and rate differences will be estimated. 
In adjusted analyses, we will use propensity score (PS) matching to balance potential 
confounders.[R13-1120] [R12-1912] PS will be derived from predicted probabilities of 
treatment initiation estimated in logistic regression models, and will be progressively enriched 
by the information obtained through an ongoing drug uilization study (BI Study No. 
1218.161) and a study assessing the impact of unmeasured confounding (BI Study No. 
1218.162). The propensity score will be used to match linagliptin initiators to initiators of 
other drug comparators on a 1:1 fixed ratio basis using a nearest-neighbor algorithm.  
Individual covariates will be tabulated and compared across matched cohorts. 
In addition, we will evaluate the balance across matched cohorts on the basis of empirical or 
established disease risk scores for selected study outcomes. [R13-0523]
Linagliptin
Comparator
PS
LinagliptinLaunch
Time
Follow-Up
Follow-Up
May 2011
Jul 2013
Jan 2014
Jul 2014
Jan 2015
Jul 2015
Jan 2016
Dec 2016
Linagliptin
Comparator
PS
Follow-Up
Follow-Up
Linagliptin
Comparator
PS
Follow-Up
Follow-Up
Linagliptin
Comparator
PS
Follow-Up
Follow-Up
Linagliptin
Comparator
PS
Follow-Up
Follow-Up
Linagliptin
Comparator
PS
Follow-Up
Follow-Up
Jul 2016
Linagliptin
Comparator
PS
Follow-Up
Follow-Up

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We will plot Kaplan-Meier curves for event-free survival and 95% confidence intervals as a 
function of the duration of use of the index hypoglycemic agent after mutivariate PS
matching. 
In addition to using propensity scores developed on the basis of investigator-identified 
covariates, we will use high-dimensional propensity scores (hdPS) in confirmatory analyses. 
The hdPS algorithm evaluates thousands of diagnoses, procedures, and pharmacy claim codes 
to identify and prioritize those covariates that serve as proxies for unmeasured confounders.  
These empirically identified confounders are combined with investigator-identified covariates 
to improve confounding adjustment.  HdPS approaches have been shown to improve validity 
in longitudinal claims data studies, particularly when combined with pre-specified covariates. 
[R13-0526] [R13-0528] [R13-0527] [R13-0525]

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8.7.3
Bias
Various design and analysis methods will be implemented to reduce the potential for bias in 
the study.  
We will employ new-user cohorts of linagliptin and comparator medications in order to 
address differences that might arise in the comparison of newer and older treatments, such as 
survivor bias and attrition of susceptibles.  
The comparator cohorts will be formed based on medications with similar clinical use profiles 
to linagliptin to reduce confounding by indications.  
We will employ propensity score matching of linagliptin and comparator cohorts in order to 
improve the balance of the cohorts with respect to numerous variables.  
1 The Cockroft-Gault formula cannot be used since information on body weight and race is not available in 
United Healthcare or Marketscan data [R96-0690]
We will use established algorithms for outcome identification and only outcomes expected to 
be ascertained well in insurance claims. The study assessing unmeasured confounding (BI 
Study No. 1218.162) will further inform the surveillance program regarding the potential for 
unmeasured confounding associated with the use of administrative claims databases, which 
have missing information on important confounders, such as body mass index, smoking, etc..
8.8
QUALITY CONTROL
All aspects of data analysis will be conducted according to standard procedures of the 
Division of Pharmacoepidemiology. Programming for this project will be conducted by a 
primary analyst and validated by a separate analyst (validation analyst).  For all data 
processing and analysis steps, the validation analyst will review the program along with input 
and output data sets, and for select steps of the project will employ double programming 
techniques to reduce the potential for programming errors.
8.9
LIMITATIONS OF THE RESEARCH METHODS
As an observational study, there are inherent limitations with respect to potential for alternate 
explanations for any observed association.
The source claims data include limitations with respect to certainty of the capture of exposure, 
covariates, and outcomes.  As a comprehensive insurance database, essentially all billable 
medical services will result in claims for reimbursement, so that the certainty of capture is tied 
to likelihood of a claim being submitted to the insurer.

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Although duration of diabetes may represent a risk factor for study outcomes, this covariate 
will be incompletely captured since the patient history in the dataset is relatively short (at least 
6 months, and an average of approximately 2 years), and a first claim within the database may 
not represent diabetes onset since the condition can be latent for some time and is typically 
not treated with hypoglycemic medications at its diagnosis.
There is potential for misclassification of dose based on healthcare utilization data, but the 
“days supply” field is expected to be fairly accurate.
New initiators are operationally defined as patients with no use in the prior 6 months. This 
does not ensure, however, that patients have never used the drug of interest; the possibility 
remains that these patients were treated at some prior time point before they enrolled in their 
insurance plan.
Medication use in United/MarketScan data - as in all administrative healthcare databases - is 
restricted to prescription drug medication. Consequently, the use of over-the-counter (OTC) 
medications (e.g., OTC aspirin) is not captured. 
Although both data United Healthcare and MarketScan databases include meaningful 
numbers of older adults 65 years and older in Medicare Advantage plans, employer-sponsored 
plans covering seniors, and Medicare supplemental insurance plans, elderly with Medicare 
Advantage might differ from the elderly with other types of Medicare coverage as they tend to
be healthier and more likely to still be employed.
8.10
OTHER ASPECTS
Any other aspect of the research method not covered by the previous sections.

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9.
PROTECTION OF HUMAN SUBJECTS
This study will be submitted to the Institutional Review Board (IRB) of the 
 
 hospital.

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10.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
Not applicable as this is a non-interventional study based on administrative data.
As stated in section VI.C.1.2.1. of GVP Module VI, for non-interventional study designs,
which are based on secondary use of data, adverse reactions reporting is not required.

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11.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The interim and final reports will consist of a description of the methods, including patient 
selection and variable definitions along with tabular summaries of cohort characteristics, 
numbers of patients receiving each anticoagulant and associated follow-up time.  Counts of 
outcomes and corresponding rates and measures of association will be presented. The tabular 
results will be followed by an interpretive summary along with a discussion of the findings 
and implications.
Manuscripts describing this work will be submitted for publication in peer-review journals. 
Findings may also be submitted for presentation at scientific conferences.

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12.
REFERENCES
Numbered list of literature or electronic references of documents referred to in the protocol. 
Sufficient information should be provided to allow retrieval of the document.
 
P10-01452
Rassen JA, Choudhry NK, Avorn J, Schneeweiss S. Cardiovascular 
outcomes and mortality in patients using clopidogrel with proton 
pump inhibitors after percutaneous coronary intervention or acute 
coronary syndrome. Circulation 2009;120:2322-9.
 
 
P12-05315
Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of 
hyperglycemia in type 2 diabetes: a patient-centered approach: 
position statement of the American Diabetes Association (ADA) and 
the European Association for the Study of Diabetes (EASD). Diabetes 
Care 2012;35:1364-79.
P12-05992
Neumiller JJ, Setter SM. Review of linagliptin for the treatment of 
type 2 diabetes mellitus. Clin Ther 2012;34:993-1005.
P13-00007
Roumie CL, Hung AM, Greevy RA, et al. Comparative effectiveness 
of sulfonylurea and metformin monotherapy on cardiovascular events 
in type 2 diabetes mellitus: a cohort study. Ann Intern Med 
2012;157:601-10.
 
 
 
P14-05386
Ziyadeh N, McAfee AT, Koro C, Landon J, Arnold Chan K. The 
thiazolidinediones rosiglitazone and pioglitazone and the risk of 
coronary heart disease: a retrospective cohort study using a US health 
insurance database. Clin Ther 2009;31:2665-77.
 
 
 

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R04-2173
Intensive blood-glucose control with sulphonylureas or insulin 
compared with conventional treatment and risk of complications in 
patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes 
Study (UKPDS) Group. Lancet 1998;352:837-53.
R10-0459
Habib ZA, Tzogias L, Havstad SL, et al. Relationship between 
thiazolidinedione use and cardiovascular outcomes and all-cause 
mortality among patients with diabetes: a time-updated propensity 
analysis. Pharmacoepidemiol Drug Saf 2009;18:437-47.
R10-0519
Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated 
for cardiovascular outcomes in oral agent combination therapy for 
type 2 diabetes (RECORD): a multicentre, randomised, open-label 
trial. Lancet 2009;373:2125-35.
 
R11-4316
Kiyota Y, Schneeweiss S, Glynn RJ, Cannuscio CC, Avorn J, 
Solomon DH. Accuracy of Medicare claims-based diagnosis of acute 
myocardial infarction: estimating positive predictive value on the 
basis of review of hospital records. Am Heart J 2004;148:99-104.
 
R11-4334
Birman-Deych E, Waterman AD, Yan Y, Nilasena DS, Radford MJ, 
Gage BF. Accuracy of ICD-9-CM codes for identifying 
cardiovascular and stroke risk factors. Medical care 2005;43:480-5.
R11-4887
Wahl PM, Rodgers K, Schneeweiss S, et al. Validation of claims-
based diagnostic and procedure codes for cardiovascular and 
gastrointestinal serious adverse events in a commercially-insured 
population. Pharmacoepidemiol Drug Saf 2010;19:596-603.
 
 
 
R12-1912
Rosenbaum PR, Rubin DB. The central role of the propensity score in 
observational studies for causal effects. Biometrica 1983:41-55.
R12-3640
Hung AM, Roumie CL, Greevy RA, et al. Comparative effectiveness 
of incident oral antidiabetic drugs on kidney function. Kidney Int 

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2012;81:698-706.
R12-3697
Lo-Ciganic W, Zgibor JC, Ruppert K, Arena VC, Stone RA. 
Identifying type 1 and type 2 diabetic cases using administrative data: 
a tree-structured model. J Diabetes Sci Technol 2011;5:486-93.
 
 
 
R13-0525
Schneeweiss S, Rassen JA, Glynn RJ, Avorn J, Mogun H, Brookhart 
MA. High-dimensional propensity score adjustment in studies of 
treatment effects using health care claims data. Epidemiology 
2009;20:512-22.
R13-0526
Huybrechts KF, Rothman KJ, Silliman RA, Brookhart MA, 
Schneeweiss S. Risk of death and hospital admission for major 
medical events after initiation of psychotropic medications in older 
adults admitted to nursing homes. CMAJ 2011;183:E411-9.
R13-0527
Rassen JA, Schneeweiss S. Using high-dimensional propensity scores 
to automate confounding control in a distributed medical product 
safety surveillance system. Pharmacoepidemiol Drug Saf 2012;21 
Suppl 1:41-9.
R13-0528
Patorno E, Bohn RL, Wahl PM, et al. Anticonvulsant medications and 
the risk of suicide, attempted suicide, or violent death. JAMA 
2010;303:1401-9.
 
 
R13-1120
Schneeweiss S. A basic study design for expedited safety signal 
evaluation based on electronic healthcare data. Pharmacoepidemiol 
Drug Saf 2010;19:858-68.
R13-3903
Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and 
cardiovascular outcomes in patients with type 2 diabetes mellitus. The 
New England journal of medicine 2013;369:1317-26.
R13-4101
Tirschwell DL, Longstreth WT, Jr. Validating administrative data in 
stroke research. Stroke 2002;33:2465-70.
 
 

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R14-1495
Waikar SS, Wald R, Chertow GM, et al. Validity of International 
Classification of Diseases, Ninth Revision, Clinical Modification 
Codes for Acute Renal Failure. J Am Soc Nephrol 2006;17:1688-94.
 
 
 
 
 
 
 
 
 
 
 
 
R14-1502
Peterson B, George SL. Sample size requirements and length of study 
for testing interaction in a 2 x k factorial design when time-to-failure 
is the outcome [corrected]. Control Clin Trials 1993;14:511-22.
 
 
 
 
 
 
 
R96-0690
Cockcroft DW, Gault MH. Prediction of creatinine clearance from 
serum creatinine. Nephron 1976;16:31-41.

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
None

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ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS
Doc.Ref. EMA/540136/2009 
ENCePP Checklist for Study Protocols (Revision 2, amended)
Adopted by the ENCePP Steering Group on 14/01/2013
The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP)
welcomes innovative designs and new methods of research. This Checklist has been developed by 
ENCePP to stimulate consideration of important principles when designing and writing a 
pharmacoepidemiological or pharmacovigilance study protocol. The Checklist
is intended to 
promote the quality of such studies, not their uniformity. The user is also referred to the ENCePP 
Guide on Methodological Standards in Pharmacoepidemiology which reviews and gives direct 
electronic access to guidance for research in pharmacoepidemiology and pharmacovigilance.
For each question of the Checklist, the investigator should indicate whether or not it has been 
addressed in the study protocol. If the answer is “Yes”, the page number(s) of the protocol where 
this issue has been discussed should be specified. It is possible that some questions do not apply to 
a particular study (for example in the case of an innovative study design). In this case, the answer 
‘N/A’ (Not Applicable) can be checked and the “Comments” field included for each section should be 
used to explain why. The “Comments” field can also be used to elaborate on a “No” answer. 
This Checklist should be included as an Annex by marketing authorisation holders when submitting 
the protocol of a non-interventional post-authorisation safety study (PASS) to a regulatory 
authority (see the Guidance on the format and content of the protocol of non-interventional post-
authorisation safety studies). Note, the Checklist is a supporting document and does not replace 
the format of the protocol for PASS as recommended in the Guidance and Module VIII of the Good 
pharmacovigilance practices (GVP). 
Study title:
Active surveillance research program for the assessment of the safety and the effectiveness of 
linagliptin
Study reference number:
Section 1: Milestones
Yes
No
N/A
Page 
Number(s)
1.1 Does the protocol specify timelines for 
1.1.1 Start of data collection1
1.1.2 End of data collection2
1.1.3 Study progress report(s) 
1.1.4 Interim progress report(s)
1.1.5 Registration in the EU PAS register
1.1.6 Final report of study results.
16
16
16-17
16-17
16
16-17
Comments:
                                                
1 Date from which information on the first study is first recorded in the study dataset or, in the case of 
secondary use of data, the date from which data extraction starts.
2 Date from which the analytical dataset is completely available.

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Section 2: Research question
Yes
No
N/A
Page 
Number(s)
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)
2.1.2 The objective(s) of the study?
18, 19
19
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to be 
generalised)
2.1.4 Which formal hypothesis(-es) is (are) to be 
tested?
2.1.5 If applicable, that there is no a priori
hypothesis?
20-21
19
Comments:
There is no a priori hypothesis.
Section 3: Study design
Yes
No
N/A
Page 
Number(s)
3.1 Is the study design described? (e.g. cohort, case-
control, randomised controlled trial, new or alternative design) 
24,40-41
3.2 Does the protocol specify the primary and 
secondary (if applicable) endpoint(s) to be 
investigated?
29-35
3.3 Does the protocol describe the measure(s) of 
effect? (e.g. relative risk, odds ratio, deaths per 1000 
person-years, absolute risk, excess risk, incidence rate ratio, 
hazard ratio, number needed to harm (NNH) per year)
41
Comments:
Section 4: Source and study populations
Yes
No
N/A
Page 
Number(s)
4.1 Is the source population described?
20-21
4.2 Is the planned study population defined in terms 
of:
4.2.1 Study time period?
4.2.2 Age and sex?
4.2.3 Country of origin?
4.2.4 Disease/indication?
4.2.5 Co-morbidity?
4.2.6 Seasonality?
20
20-21
2
20-21
22-24
4.3 Does the protocol define how the study population 
will be sampled from the source population? (e.g. 
event or inclusion/exclusion criteria)  
20-21
Comments:
The concept of seasonality is not relevant to diabetes, the condition under study.

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Section 5: Exposure definition and measurement
Yes
No
N/A
Page 
Number(s)
5.1 Does the protocol describe how exposure is 
defined and measured? (e.g. operational details for 
defining and categorising exposure)
25-27
5.2 Does the protocol discuss the validity of exposure 
measurement? (e.g. precision, accuracy, prospective 
ascertainment, exposure information recorded before the 
outcome occurred, use of validation sub-study)
44
5.3 Is exposure classified according to time windows?
(e.g. current user, former user, non-use)
25-27
5.4 Is exposure classified based on biological 
mechanism of action and taking into account the 
pharmacokinetics and pharmacodynamics of the 
drug?
27-29
5.5 Does the protocol specify whether a dose-
dependent or duration-dependent response is 
measured?
42
Comments:
Section 6: Endpoint definition and measurement
Yes
No
N/A
Page 
Number(s)
6.1 Does the protocol describe how the endpoints are 
defined and measured? 
30-33
6.2 Does the protocol discuss the validity of endpoint 
measurement? (e.g. precision, accuracy, sensitivity, 
specificity, positive predictive value, prospective or 
retrospective ascertainment, use of validation sub-study)
30-33
Comments:
Section 7: Confounders and effect modifiers
Yes
No
N/A
Page 
Number(s)
7.1 Does the protocol address known confounders?
(e.g. collection of data on known confounders, methods of 
controlling for known confounders)
35,57-75
7.2 Does the protocol address known effect modifiers?
(e.g. collection of data on known effect modifiers, anticipated 
direction of effect)
42-43
Comments:
Section 8: Data sources
Yes
No
N/A
Page 
Number(s)
8.1 Does the protocol describe the data source(s) 
used in the study for the ascertainment of:
8.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-face 
interview, etc.)
21,44

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Section 8: Data sources
Yes
No
N/A
Page 
Number(s)
8.1.2 Endpoints? (e.g. clinical records, laboratory markers 
or values, claims data, self-report, patient interview including 
scales and questionnaires, vital statistics, etc.)
8.1.3 Covariates?
30-33
57-75
8.2 Does the protocol describe the information 
available from the data source(s) on:
8.2.1 Exposure? (e.g. date of dispensing, drug quantity, 
dose,  number of days of supply prescription, daily dosage,  
prescriber)
8.2.2 Endpoints? (e.g. date of occurrence, multiple event, 
severity measures related to event)
8.2.3 Covariates? (e.g. age, sex, clinical and drug use 
history, co-morbidity, co-medications, life style, etc.)
20,44
30-33,44
57-75,44
8.3 Is a coding system described for:
8.3.1 Diseases? (e.g. International Classification of 
Diseases (ICD)-10)
8.3.2 Endpoints? (e.g. Medical Dictionary for Regulatory 
Activities (MedDRA) for adverse events)
8.3.3 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC)Classification System)
52-57
30-33
20-21,55-6
8.4 Is the linkage method between data sources 
described? (e.g. based on a unique identifier or other)
Comments:
No data linkages are planned.
Section 9: Study size and power
Yes
No
N/A
Page 
Number(s)
9.1 Is sample size and/or statistical power calculated? 
36-39
Comments:
Section 10: Analysis plan
Yes
No
N/A
Page 
Number(s)
10.1 Does the plan include measurement of excess 
risks?
41
10.2 Is the choice of statistical techniques described? 
41-42
10.3 Are descriptive analyses included?
41
10.4 Are stratified analyses included?
42-43
10.5 Does the plan describe methods for adjusting for 
confounding?
41-42
10.6 Does the plan describe methods addressing 
effect modification?
42-43
Comments:

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Section 11: Data management and quality 
control
Yes
No
N/A
Page 
Number(s)
11.1 Is information provided on the management of 
missing data?
43
11.2 Does the protocol provide information on data 
storage? (e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving)
40
11.3 Are methods of quality assurance described?
44
11.4 Does the protocol describe possible quality issues 
related to the data source(s)?
44
11.5 Is there a system in place for independent 
review of study results? 
48
Comments:
Section 12: Limitations
Yes
No
N/A
Page 
Number(s)
12.1 Does the protocol discuss:
12.1.1 Selection biases?
12.1.2 Information biases?
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods)
43-44
43-44
12.2 Does the protocol discuss study feasibility? (e.g. 
sample size, anticipated exposure, duration of follow-up in a 
cohort study, patient recruitment)
37-39
12.3 Does the protocol address other limitations? 
44
Comments:
Section 13: Ethical issues
Yes
No
N/A
Page 
Number(s)
13.1 Have requirements of Ethics 
Committee/Institutional Review Board approval 
been described?
46
13.2 Has any outcome of an ethical review procedure 
been addressed?
13.3 Have data protection requirements been 
described?
40
Comments:
The study has been submitted to and approved by the Institutional Review Board of 
Section 14: Amendments and deviations
Yes
No
N/A
Page 
Number(s)
14.1 Does the protocol include a section to document 
15

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Section 14: Amendments and deviations
Yes
No
N/A
Page 
Number(s)
future amendments and deviations? 
Comments:
Section 15: Plans for communication of study 
results
Yes
No
N/A
Page 
Number(s)
15.1 Are plans described for communicating study 
results (e.g. to regulatory authorities)?
47
15.2 Are plans described for disseminating study 
results externally, including publication?
48
Comments:
Name of the main author of the protocol: ___________________________
Date: 6/4/2014
Signature: ___________________________

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ANNEX 3. ADDITIONAL INFORMATION
ANNEX 3.1 OTHER HYPOGLYCEMIC AGENTS
The primary exposures of interest in this study are linagliptin, other DPP-4 inhibitors 
(saxagliptin or sitagliptin), pioglitazone, and 2nd generation sulfonylureas.  In addition to these 
cohort-defining hypoglycemic agents, the following glucose-lowering drugs will be 
considered for the identification of monotherapy versus combination therapy, subgroup 
analyses, and characteristics balancing of exposure groups of interest.  This table will be 
updated as additional hypoglycemic agents are approved.
Class
Drug
FDA approval 
date
Combination products
Sodium glucose 
co-transporter 
(SGLT2) 
inhibitors
Canagliflozin
March 29, 2013
N/A
Dapagliflozin
Jan 8, 2014
N/A
Glitazones
Rosiglitazone
May 25, 1999
+ metformin (Avandamet)
+ glimepiride (Avandaryl)
Biguanides
Metformin
Mar 3, 1995
+ linagliptin
+ sitagliptin
+ saxagliptin
+ rosiglitazone
+ pioglitazone
+ glipizide
+ glyburide
1st Generation 
Sulfonylureas
Chlorpropamide
Prior to Jan 1, 
1982
N/A
Acetohexamide
1964
N/A
Tolazamide
Jan 2, 1986
N/A
Tolbutamide
Prior to Jan 1, 
1982
N/A
Alpha-
glucosidase 
inhibitors
Acarbose
Sep 6, 1995
N/A
Miglitol
Dec 18, 1996
N/A
Meglitinides
Nateglinide
Dec 22, 2000
N/A
Repaglinide
Dec 22, 1997
+ metformin (Prandimet)
Glucagon-like 
peptide-1 
(GLP-1) 
receptor 
agonists
Exenatide 
Apr 28, 2005
N/A
Liraglutide
Jan 25, 2010
N/A
Injectable 
amylin 
analogues
Pramlintide
Mar 16, 2005
N/A

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* Use of these agents does not qualify subjects for cohort inclusion.  However, use of these agents is relevant in defining the 
subgroup of treatment naive new users and in categorizing monotherapy versus combination therapy.
Class
Type
Drug
Insulin
Mixed insulin
insulin human isophane (NPH)/insulin human regular
Insulin lispro/insulin lispro protamine
insulin aspart/insulin aspart protamine
Short-acting 
insulin
insulin human regular
insulin human regular, buffered
Rapid-acting 
insulin
insulin aspart, recombinant
insulin glulisine
insulin lispro, recombinant
Intermediate-
acting insulin
Insulin human isophane (NPH)
Insulin human zinc
Long-acting 
insulin
Insulin detemir
Insulin glargine, recombinant
Insulin human zinc, extended

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ANNEX 3.2 DEFINITIONS OF STUDY COVARIATES
Unless specified otherwise, covariates are based on 1 in- or outpatient diagnosis in any 
position, since we strive for high sensitivity for covariate definitions.
Covariate
Definition (unless otherwise noted, inpatient or outpatient dx, any 
position)
Number of patients
Number naïve new users
CHARACTERISTICS OF 
INITIATION
Initiation as monotherapy
The drug of interest is initiated as monotherapy
Concomitant initiation of other specific 
hypoglycemic agents – Any agent
Concomitant initiation of other specific hypoglycemic agents on the day of 
initiation of the drug of interest. Concomitant initiation is defined as first use 
(no use in prior 6 months) on the same day
Any agent is linagliptin, sitagliptin, saxagliptin, metformin, sulfonylureas, 
glitazones, meglitinides, AGI, non-insulin injected agents, or insulin
Concomitant initiation of linagliptin
Concomitant initiation of sitagliptin
Concomitant initiation of saxagliptin
Concomitant initiation of metformin
Concomitant initiation of sulfonylureas
Concomitant initiation of glitazones
Concomitant initiation of meglitinides
Concomitant initiation of AGI
Concomitant initiation of non-insulin 
injected agents (exenatide, liraglutide, 
albiglutide)
SGLT2 inhibitors (Canagliflozin, dapagliflozin)
Concomitant initiation of insulin – any 
formulation
Any formulation is Short-acting insulin, Rapid-acting insulin, Intermediate-
acting insulin, Long-acting insulin, or Insulin mixtures
Concomitant initiation of short-acting insulin
Insulin human Regular
Concomitant initiation of rapid-acting insulin
Insulin lispro, 
Insulin aspart 
Insulin glulisine 
Concomitant initiation of intermediate-acting insulin
Insulin human isophane (NPH)
Insulin human zinc
Concomitant initiation of long-acting insulin
Insulin determir
Insulin glargine 
Insulin human zinc, extended
Concomitant initiation of insulin mixtures
Insulin lispro protamine/insulin lispro
Insulin aspart protamine/insulin aspart
NPH/Regular
Initiation as component of dual therapy
The drug of interest is initiated in combination with 1 other drug only, i.e. 
only 2 medications are initiated on the same date among linagliptin, 
sitagliptin, saxagliptin, metformin, sulfonylureas, glitazones, meglitinides, 
AGI, non-insulin injected agents, or insulin)
Initiation as component of ≥3 therapies
The drug of interest is initiated in combination with 2 or more other drugs, 
i.e. only 3 or more medications are initiated on the same date among 
linagliptin, sitagliptin, saxagliptin, metformin, sulfonylureas, glitazones, 
meglitinides, AGI, non-insulin injected agents, or insulin)
Initiation as fixed-dose combination of two 
agents
The drug of interest is initiated as fixed-dose combination of two agents, 
regardless of the number of agents initiated on the same date
PRIOR USE OF OTHER 
HYPOGLYCEMIC AGENTS
Previous use of other specific hypoglycemic 
agents – Any agent
Use of other specific hypoglycemic agents at any point during the 6 months 
preceding (and including date of) dispensing of the drug of interest
Any agent is linagliptin, sitagliptin, saxagliptin, metformin, sulfonylureas, 
glitazones, meglitinides, AGI, non-insulin injected agents, or insulin
Previous use of linagliptin
Previous use of sitagliptin

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… (List as above)
Current use of other specific hypoglycemic 
agents – Any agent
Current use of other specific hypoglycemic agents on the day of initiation of 
the drug of interest (i.e., the agent has been initiated prior to and is 
continuously used on the day of initiation of the drug of interest)
Any agent is linagliptin, sitagliptin, saxagliptin, metformin, sulfonylureas, 
glitazones, meglitinides, AGI, non-insulin injected agents, or insulin
Concomitant use of linagliptin
Concomitant use of sitagliptin
… (List as above)
Past use of other specific hypoglycemic 
agents – Any agent
Any use in the 6-month period prior to the day of initiation of the drug of 
interest (i.e., the agent has been initiated prior to and is NOT continuously 
used on the day of initiation of the drug of interest)
Any agent is linagliptin, sitagliptin, saxagliptin, metformin, sulfonylureas, 
glitazones, meglitinides, AGI, non-insulin injected agents, or insulin
Past use of linagliptin
Past use of sitagliptin
… (List as above)
DEMOGRAPHICS
Age
Age category 18-35
Age category 36-49
Age category 50-64
Age category 65-74
Age category 75+
Sex
Female, Male
Baseline year
Comorbidity score, Charlson
HEALTH CARE UTILIZATION
Total N distinct non-insulin hypoglicemic agents 
prescribed
Total N distinct pharmacological agents prescribed
N physician visits
Hospitalization (Y/N)
N hospitalizations
N hospital days
Hospitalization in 30 days prior to treatment initiation
Total N distinct ICD9 diagnoses at the 3rd digit level
Number of laboratory tests ordered
Number of hemoglobin A1C tests ordered
CPT4: 83036 (HEMOGLOBIN; GLYCOSYLATED (A1C)
Number of glucose tests ordered
82947
GLUCOSE; QUANTITATIVE, BLOOD (EXCEPT REAGENT 
STRIP)
82948
GLUCOSE; BLOOD, REAGENT STRIP
82962
GLUCOSE, BLOOD, GLUCOSE MONITORING DEVICE(S) 
CLEARED BY FDA SPECIFICALLY FOR HOME USE
Number of lipid tests ordered
V7791 - SCREENING FOR LIPOID DISORDERS
80061 - LIPID PROFILE
82465 - ASSAY CHOLEST SERUM/WHOLE BLD TTL
83718 - BLOOD LIPOPROTEIN ASSAY HDL
83719 - BLOOD LIPOPROTEIN ASSAY VLDL
83721 - BLOOD LIPOPROTEIN ASSAY LDL
84478 - ASSAY BLOOD TRIGLYCERIDES
Number of creatinine tests ordered
CPT4: 
82565
CREATININE; BLOOD
Mammography
CPT: 76082 (COMPUTER AIDED DETECTION WITH FURTHER 
PHYSICIAN REVIEW FOR INTERPRETATION WITH OR WITHOUT 
DIGITIZATION OF FILM RADIOGRAPHIC IMAGES, DIAGNOSTIC 
MAMMOGRAPHY), 76083 (COMPUTER AIDED DETECTION WITH 
FURTHER PHYSICIAN REVIEW FOR INTERPRETATION WITH OR 
WITHOUT DIGITIZATION OF FILM RADIOGRAPHIC IMAGES, 
SCCREENING MAMMOGRAPHY), 76092 (SCREENING 
MAMMOGRAPHY, BILAT (2 VIEW FILM STUDY, EACH BREAST) 
HCPS: G0202 (SCREENING MAMMOGRAPHY, PRODUCING DIRECT 
DIGITAL IMAGE, BILATERAL, ALL VIEWS), G0203 (DIAGNOSTIC 
MAMMOGRAPHY. PRODUCING DIRECT DIGITAL IMAGE, 
BILATERAL, ALL VIEWS)
Pap test
HCPCS:  Q0091 (SCREENING PAPANICOLAOU SMEAR; OBTAINING,
PREPARING AND CONVEYANCE OF CERVICAL OR VAGINAL 

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SMEAR TO LAB), P3000 (UP TO THREE SMEARS BY TECHNICIAN 
UNDER PHYSICIAN SUPERVISION), P3001 (UP TO THREE SMEARS 
REQUIRING INTERPRETATION BY PHYSICIAN), G0123 (SCREENING 
CYTOPATHOLOGY, CERVICAL OR VAGINAL, ANY REPORTING 
SYSTEM, COLLECTED IN PRESERVING FLUID, AUTOMATED THIN 
LAYER PREP, BY CYTOTECHNOLOGIST), G0124 (SCREENING 
CYTOPATHOLOGY, CERVICAL OR VAGINAL, REQUIRING 
PHYSICIAN INTERPRETATION), G0141 (SCREENING 
CYTOPATHOLOGY, SMEARS, CERVICAL OR VAGINAL, 
PERFORMED BY AUTOMATED SYSTEM, WITH MANUAL 
RESCREENING, REQUIRING INTERPRETATION BY PHYSICIAN) , 
G0143 (MANUAL SCREENING, AND RESCREENING BY 
CYTOTECHNOLOGIST UNDER PHYSICIAN SUPERVISION), G0144 
(SCREENING BY AUTOMATED SYSTEM UNDER PHYSICIAN 
SUPERVISION), G0145 (SCREENING BY AUTOMATED SYSTEM AND 
MANUAL RESCREENING UNDER PHYSICIAN SUPERVISION), G0147 
(SCREENING CYTOPATHOLOGY SMEARS,  CERVICAL OR 
VAGINAL, PERFORMED BY AUTOMATED SYSTEM UNDER 
PHYSICIAN SUPERVISION), G0148 (SCREENING CYTOPATHOLOGY 
SMEARS, CERVICAL OR VAGINAL, PERFORMED BY AUTOMATED 
SYSTEM WITH MANUAL RESCREENING), 88141 – 88158 
(CYTOPATHOLOGY, CERVICAL OR VAGINAL (ANY REPORTING 
SYSTEM), REQUIRING INTERPRETATION BY PHYSICIAN; 
CYTOPATHOLOGY, CERVICAL OR VAGINAL (ANY REPORTING 
SYSTEM), COLLECTED IN PRESERVATIVE FLUID, AUTOMATED 
THIN LAYER PREPARATION; MANUAL SCREENING UNDER 
PHYSICIAN SUPERVISION; CYTOPATHOLOGY, CERVICAL OR 
VAGINAL, (ANY REPORTING SYSTE) COLLECTED IN 
PRESERVATIVE FLUID, AUTOMATED THING LAYER 
PREPARATION, WITH MANUAL SCREENING AND RESCREENING 
UNDER PHYSICIAN SUPERVISION; CYTOPATHOLOGY SMEARS, 
CERVICAL OR VAGINAL, SCREENING BY SUTOMATED SYSTEM 
UNDER PHYSICIAN SUPERVISION; CYTOPATHOLOGY SMEARS, 
CERVICAL OR VAGINAL, SCREENING BY AUTOMATED SYSTEM 
WITH MANUAL RESCREENING UNDER PHYSICIAN SUPERVISION; 
CYTOPATHOLOGY, SLIDES, CERVICAL OR VAGINAL, MANUAL 
SCREENING UNDER PHYSICIAN SUPERVISION; 
CYTOPATHOLOGY; SLIDES, CERVICAL OR VAGINAL, WITH 
MANUAL SCREENING AND COMPUTER ASSISTED RESCREENING 
UNDER PHYSICIAN SUPERVISION; CYTOPATHOLOGY, SLIDES, 
CERVICAL OR VAGINAL, WITH MANUAL SCREENING AND 
COMPUTER ASSISTED RESCREENING USING CELL SELECTION 
AND REVIEW UNDER PHYSICIAN SUPERVISION; 
CYTOPATHOLOGY, SLIDES, CERVICAL OR VAGINAL, DEFINITIVE 
HORMONAL EVALUATION (EG, MATURATION INDEX, 
KARYOPTKNOTIC INDEX, ESTROGENIC INDEX)), 88164 – 88167 
(CYTOPATHOLOGY, SLIDES, CERVICAL OR VAGINAL, BETHESDA 
SYSTEM, MANUAL SCREENING UNDER PHYSICIAN SUPERVISION; 
CYTOPATHOLOGY, SLIDES, CERVICAL OR VAGINAL, THE 
BETHESDA SYSTEM, WITH MANUAL SCREENING AND 
RESCREENING UNDER PHYSICIAN SUPERVISION; 
CYTOPATHOLOGY, SLIDES, CERVICAL OR VAGINAL, THE 
BETHESDA SYSTEM, WITH MANUAL SCREENING AND COMPUTER 
ASSISTED RESCREENING UNDER PHYSICIAN SUPERVISION; 
CYTOPATHOLOGY, SLIDES, CERVICAL OR VAGINAL, THE 
BETHESDA SYSTEM, WITH MANUAL SCREENING AND COMPUTER 
ASSISTED RESCREENING USING CELL SELECTION AND REVIEW 
UNDER PHYSICIAN SUPERVISION), 88174 – 88175 
(CYTOPATHOLOGY, CERVICAL OR VAGINAL, ANY REPORTING 
SYSTEM, COLLECTED IN PRESERVATIVE FLUID, AUTOMATED 
THIN LAYER PREPARATION, SCREENING BY AUTOMATED 
SYSTEM, UNDER PHYSICIAN SUPERVISION; CYTOPATHOLOGY, 
CERVICAL OR VAGINAL, ANY REPORTING SYSTEM, COLLECTED 
IN PRESERVATIVE FLUID, AUTOMATED THIN LAYER 
PREPARATION, WITH SCREENING BY AUTOMATED SYSTEM AND 
MANUAL RESCREENING OR REVIEW, UNDER PHYSICIAN 
SUPERVISION)
PSA test
HCPCS: G0103 (PROSTATE CANCER SCREENING; PROSTATE 
SPECIFIC ANTIGEN TEST (PSA))
CPT: 84153, 84152 – 84154 (PROSTATE SPECIFIC ANTIGEN (PSA): 
COMPLEXED (DIRECT MEASUREMENT) or TOTAL or FREE)
Colonoscopy
45.23 (COLONOSCOPY)
HCPCS: G0105 (COLORECTAL CANCER SCREENING; 

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COLONOSCOPY ON INDIVIDUAL AT HIGH RISK), G0121 
(COLORECTAL CANCER SCREENING; COLONOSCOPY ON 
INDIVIDUAL NOT MEETING CRITERIA FOR HIGH RISK)
CPT: 45378-45392 (COLONSCOPY, FLEXIBLE, PROXIMAL TO 
SPLENIC FLEXURE, DIAGNOSTIC, WITH OR WITHOUT 
COLLECTION OF SPECIMENS BY BRUSHING OR WASHING, WITH 
OR WITHOUT COLON DECOMPRESSION; COLONSCOPY, FLEXIBLE, 
PROXIMAL TO SPLENIC FLEXURE, WITH REMOVAL OF FOREIGN 
BODY; COLONOSCOPY, FLEXIBLE, PROXIMAL TO SPLENIC 
FLEXURE, WITH BIOPSY, SINGLE OR MULTIPLE; COLONOSCOPY, 
FLEXIBLE, PROXIMAL TO SPLENIC FLEXURE, WITH DIRECTED 
SUBMUCOSAL INJECTIONS, ANY SUBSTANCE; COLONOSCOPY 
FLEXIBLE, PROXIMAL TO SPLENIC FLEXURE, WITH CONTROL OF 
BLEEDING; COLONOSCOPY, FLEXIBLE, PROXIMAL TO SPLENIX 
FLEXURE, WITH ABLATION OF TUMORS POLYPS OR OTHER 
LESIONS NOT AMEABLE TO REMOVAL BY HOT BIOPSY FORCEPS, 
BIPOLAR CAUTERY OR SNARE TECHNIQUE; COLONOSCOPY, 
FLEXIBLE, PROXIMAL TO SPLENIC FLEXURE, WITH REMOVAL OF 
TUMORS POLYPS OR OTHER LESIONS BY HOT BIOPSY FORCEPS 
OR BIPOLAR CAUTERY; COLONOSCOPY, FLEXIBLE, PROXIMAL 
TO SPLENIC FLEXURE, WITH REMOCAL OF TUMORS POLYPS OR 
OTHER LESIONS BY SNARE TECHNIQUE; COLONOSCOPY, 
FLEXIBLE, PROXIMAL TO SPLENIC FLEXURE, WITH DILATION BY 
BALLOON, ONE OR MORE STRUCTURES; COLONOSCOPY, 
FLEXIBLE, PROXIMAL TO SPLENIC FLEXURE, WITH 
TRANSECNDOSCOPIC STENT PLACEMENT INCLDUING 
PREDILATION; COLONOSCOPY, FLEXIBLE, PROXIMAL TO 
SPLENIC FLEXURE, WITH ENDOSCOPIC ULTRASOUND 
EXAMINATION; COLONOSCOPY, FLEXIBLE, PROXIMAL TO 
SPLENIC FLEXURE, WITH TRANSENDOSCOPIC ULTRASOUND 
GUIDED INTRAMURAL OR TRANSMURAL FINE NEEDLE 
ASPIRATION/BIOPSY)
Fecal occult blood test
HCPCS: G0107 (COLORECTAL CANCER SCREENING; FECAL-
OCCULT BLOOD TEST, 1-3 SIMULTANEOUS DETERMINATIONS) 
G0328 (COLORECTAL CANCER SCREENING; FECAL OCCULT 
BLOOD TEST, IMMUNOASSAY, 1-3 SIMULTANEOUS)
CPT: 82270 (BLOOD, OCCULT, BY PEROXIDASE ACTIVITY (EG, 
GUAIAC), QUALITATIVE; FECES, CONSECUTIVE COLLECTED 
SPECIMENS WITH SINGLE DETERMINATION), 82274 (BLOOD, 
OCCULT, BY FECAL HEMOGLOBIN DETERMINATION BY 
IMMUNOASSAY, QUALITATIVE, FECES, 1-3 SIMULTANEOUS 
DETERMINATIONS)
Flu shot
CPT: 90655 – 90660 (INFLUENZA VIRUS VACCINE, SPLIT VIRUS, 
PRESERVATIVE FREE, WHEN ADMINISTERED TO CHILDREN 6-35 
MONTHS OF AGE, FOR INTRAMUSCULAR USE; INFLUENZA VIRUS 
VACCINE, SPLIT VIRUS, PRESERVATIVE FREE, WHEN 
ADMINISTERED TO INDIVIDUALS 3 YEARS AND OLDER, FOR 
INTRAMUSCULAR USE; INFLUENZA VIRUS VACCINE, SPLIT 
VIRUS, WHEN ADMINISTERED TO CHILDREN 6-35 MONTHS OF 
AGE, FOR INTRAMUSCULAR USE; INFLUENZA VIRUS VACCINE, 
SPLIT VIRUS, WHEN ADMINISTERED TO INDIVIDUALS 3 YEARS 
OF AGE AND OLDER, FOR INTRAMUSCULAR USE; INFLUENZA 
VIRUS VACCINE, WHOLE VIRUS, IM/JET INJECTION USE; 
INFLUENZA VIRUS VACCINE, LIVE, FOR INTRANASAL USE), 90724 
(INFLUENZA VIRUS VACCINE) 
HCPCS: G0008 (ADMINISTRATION OF INFLUENZA VIRUS 
VACCINE)
ICD-9 diagnosis: V04.8 (NEED FOR PROPHYLACTIC VACCINATION 
AND INOCULATION AGAINST OTHER VIRAL DISEASES), V04.81 
(NEED FOR PROPHYLACTIC VACCINATION AND INOCULATION 
AGAINST INFLUENZA), V06.6 (NEED FOR PROPHYLACTIC 
VACCINATION AND INOCULATION AGAINST STREPTOCOCCUS 
PNEUMONIAE AND INFLUENZA)
Pneumococcal vaccine
90669 (PNEUMOCOCCAL CONJUGATE VACCINE, 7 VALENT, FOR 
INTRAMUSCULAR USE), 90670 (PNEUMOCOCCAL CONJUGATE 
VACCINE, 13 VALENT, FOR INTRAMUSCULAR USE),
90732 (PNEUMOCOCCAL POLYSACCHARIDE VACCINE, 23-
VALENT, ADULT/IMMUNOSUPPRESSED PATIENT DOSAGE, 
SUBQ/IM USE)
G0009 (ADMINISTRATION OF PNEUMOCOCCAL 
POLYSACCHARIDE VACCINE)
V03.82 (NEED FOR PROPHYLACTIC VACCINATION AND 
INOCULATION AGAINST STREPTOCOCCUS PNEUMONIAE)

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BMD testing 
CPT: 76070 (CT BONE MINERAL DENSITY STUDY, 1+ SITES; AXIAL 
SKELETON), 76075 (DEXA, BONE DENSITY STUDY, 1+ SITES; 
AXIAL SKELETON), 76076 (DEXA, BONE DENSITY STUDY, 1+ SITES 
;APPENDICULAR SKELETON), 76977 (US BONE DENSITY 
MEASUREMENT & INTERPRETATION, PERIPHERAL SITE(S), ANY 
METHOD)
Number of electrocardiograms 
ICD-9 procedure code: 89.51 (RHYTHM ELECTROCARDIOGRAM), 
89.52 (ELECTROCARDIOGRAM)
CPT4: 93000 (ELECTROCARDIOGRAM, ROUTINE ECG WITH AT 
LEAST 12 LEADS; WITH INTERPRETATION AND REPORT), 93005 
(ELECTROCARDIOGRAM, ROUTINE ECG WITH AT LEAST 12 
LEADS; TRACING ONLY, WITHOUT INTERPRETATION AND 
REPORT), 93010 (ELECTROCARDIOGRAM, ROUTINE ECG WITH AT 
LEAST 12 LEADS; INTERPRETATION, AND REPORT ONLY)
Long-term (current) use of insulin
V58.67
Use of glucose test strips
CPT: 82948 (GLUCOSE; BLOOD, REAGENT STRIP)
LABORATORY TESTS
HbA1c (%)
Creatinine (mg/dl)
eGFR (ml/min per 1.73 m2)
Total cholesterol (mg/dl)
HDL level (mg/dl)
LDL level (mg/dl)
Triglyceride level (mg/dl)
COMORBIDITIES AT BASELINE
Diabetes during pregnancy
648.0x
PCOS
256.4x
Female Infertility
628.x
Precocious puberty
259.1
Hyperglycemia
790.29
Diabetic ketoacidosis
250.1x
Hyperosmolar hyperglycemic nonketotic syndrome 
(HONK)
250.2x
Diabetes with coma
250.3x, excluding 250.30 (DIABETES WITH OTHER COMA)
Hypoglycemic coma
251.0 (HYPOGLYCEMIC COMA), 250.30 (DIABETES WITH OTHER 
COMA)
Hypoglycemia
251.1 (OTHER SPECIFIED HYPOGLYCEMIA), 251.20 
(HYPOGLYCEMIA UNSPECIFIED), 962.30 (POISONING BY INSULINS 
AND ANTIDIABETIC AGENTS), 775.60 (NEONATAL 
HYPOGLYCEMIA)
Also, 250.8x (DIABETES WITH OTHER SPECIFIED 
MANIFESTATIONS) as long as none of the following codes are co-
diagnoses:  259.8 (OTHER SPECIFIED ENDOCRINE DISORDERS), 272.7 
(LIPIDOSES), 681.xx (CELLULITIS AND ABSCESS OF FINGER AND 
TOE), 682.xx (OTHER CELLULITIS AND ABSCESS), 686.9x 
(UNSPECIFIED LOCAL INFECTION OF SKIN AND SUBCUTANEOUS 
TISSUE), 707.xx (CHRONIC ULCER OF SKIN), 709.3 (DEGENERATIVE 
SKIN DISORDERS), 730.0-730.2 (OSTEOMYELITIS PERIOSTITIS AND 
OTHER INFECTIONS INVOLVING BONE; CHRONIC 
OSTEOMYELITIS; UNSPECIFIED OSTEOMYELITIS), 731.8 (OTHER 
BONE INVOLVEMENT IN DISEASES CLASSIFIED ELSEWHERE)
Diabetic retinopathy
362.01-362.07 (DIABETIC RETINOPATHY: BACKGROUND, 
PROLIFERATIVE, NONPROLIFERATIVE, MILD 
NONPROLIFERATIVE, MODERATE NONPROLIFERATIVE, SEVERE; 
DIABETIC MACULAR EDEMA)
Diabetic nephropathy NOS
583.81
Opthalmology visit
ICD-9 procedure code:  14.11 (DIAGNOSTIC ASPIRATION OF 
VITREOUS), 14.19 (OTHER DIAGNOSTIC PROCEDURES ON RETINA, 
CHOROID, VITREOUS, AND POSTERIOR CHAMBER), 14.21-14.29 
(DESTRUCTION OF CHOIORETINAL LESION BY DIATHERMY, BY 
CRYOTHERAPY, BY XENON ARC PHOTOCOAGULATION, BY 
LASER PHOTOCOLAGULATION, BY UNSPECIFIED COAGULATION, 
BY RADIATION THERAPY, BY IMPLANTATION OF RADIATION 
SOURCE, BY OTHER), 14.31-14.35 (REPAIR OF RETINAL TEAR BY 
IATHERMY, BY CRYOTHERAPY, BY XENON ARC 
PHOTOCOAGULATION, BY LASER PHOTOCOAGULATION, BY 
PHOTOCOAGULATION OF UNSPECIFIED TYPE), 14.39 (OTHER 
REPAIR OF RETINAL TEAR), 14.41 (SCLERAL BUCKLING WITH 
IMPLANT), 14.49 (OTHER SCLERAL BUCKLING), 14.51-14.55 
(REPAIR OF RETINAL DETACHMENT WITH DIATHERMY, WITH 
CRYOTHERAPY, WITH XENON ARC PHOTOCOAGULATION, WITH 
LASER PHOTOCOAGULATION), 14.59 (OTHER), 14.9 (OTHER 

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OPERATIONS OF RETINA, CHOROID, AND POSTERIOR CHAMBER), 
95.02-95.04 (COMPREHENSIVE EYE EXAMINATION, 
OPTHAMALOGIC WORK-UP, EYE EXAM UNDER ANESTHESIA), 
95.11 (FUNDUS PHOTOGRAPHY), 95.12 (FLUORESCEIN 
ANGIOGRAPHY OR ANGIOSCOPY OF EYE), 95.16 (P32 AND OTHER 
TRACER STUDIES OF EYE)
CPT-4 code: 67028 (INTRAVITREAL INJECTION OF A 
PHARMACOLOGIC AGENT (SEPARATE PROCEDURE), 67038-67040 
(VITRECTOMY, MECHANICAL, PARS PLANA APPROACH; WITH 
ENDOLASER PANRETINAL PHOTOCOAGULATION), 67101 (REPAIR 
OF RETINAL DETACHMENT, 1 OR MORE SESSIONS; 
CRYOTHERAPY OR DIATHERMY, WITH OR WITHOUT DRAINAGE 
OF SUBRETINAL FLUID), 67105 (REPAIR OF RETINAL 
DETACHMENT, 1 OR MORE SESSIONS; PHOTOCOAGULATION, 
WITH OR WITHOUT DRAINAGE OF SUBRETINAL FLUID), 67107 
(REPAIR OF RETINAL DETACHMENT; SCLERAL BUCKLING (SUCH 
AS LAMELLAR SCLERAL, DISSECTION, IMBRICATION OR 
ENCIRCLING PROCEDURE) 67108 (REPAIR OF RETINAL 
DETACHMENT; WITH VITRECTOMY, ANY METHOD, WITH OR 
WITHOUT AIR OR GAS TAMPONADE, FOCAL ENDOLASER 
PHOTOCOAGULATION),  67110 (REPAIR OF RETINAL 
DETACHMENT; BY INJECTION OF AIR OR OTHER GAS (EG, 
PNEUMATIC RETINOPEXY), 67112 (REPAIR OF RETINAL 
DETACHMENT; BY SCLERAL BUCKLING OR VITRECTOMY, ON 
PATIENT HAVING PREVIOUS IPSILATERAL RETINAL 
DETACHMENT REPAIRS), 67141 (PROPHYLAXIS OF RETINAL 
DETACHMENT (EG, RETINAL BREAK, LATTICE DEGENERATION) 
WITHOUT DRAINAGE, 1 OR MORE SESSIONS; CRYOTHERAPY), 
67145 (PROPHYLAXIS OF RETINAL DETACHMENT (EG, RETINAL 
BREAK, LATTICE DEGENERATION) WITHOUT DRAINAGE, 1 OR 
MORE SESSIONS; PHOTOCOAGULATION), 67208 (DESTRUCTION 
OF LOCALIZED LESION OF RETINA (EG, MACULAR EDEMA, 
TUMORS), 1 OR MORE SESSIONS; CRYOTHERAPY, DIATHERMY), 
67210 (DESTRUCTION OF LOCALIZED LESION OF RETINA (EG, 
MACULAR EDEMA, TUMORS), 1 OR MORE SESSIONS; 
PHOTOCOAGULATION), 67218 (DESTRUCTION OF LOCALIZED 
LESION OF RETINA (EG, MACULAR EDEMA, TUMORS), 1, OR MORE 
SESSIONS; RADIATION BY IMPLANTATION OF SOURCE), 67227 
(DESTRUCTION OF EXTENSIVE OR PROGRESSIVE RETINOPATHY 
(EG, DIABETIC RETINOPATHY), 1 OR MORE SESSIONS, 
CRYOTHERAPY, DIATHERMY), 67228 (TREATMENT OF EXTENSIVE 
OR PROGRESSIVE RETINOPATHY, 1 OR MORE SESSIONS; (EG, 
DIABETIC RETINOPATHY), PHOTOCOAGULATION), 92002 
(OPHTHALMOLOGICAL SERVICES: MEDICAL EXAMINATION AND 
EVALUATION WITH INITIATION OF DIAGNOSTIC AND 
TREATMENT PROGRAM; INTERMEDIATE), 92004 
(OPHTHALMOLOGICAL SERVICES: MEDICAL EXAMINATION AND 
EVALUATION WITH INITIATION OF DIAGNOSTIC AND 
TREATMENT PROGRAM; COMPREHENSIVE), 92012 
(OPHTHALMOLOGICAL SERVICES: MEDICAL EXAMINATION AND 
EVALUATION, WITH INITIATION OR CONTINUATION OF 
DIAGNOSTIC AND TREATMENT PROGRAM),  92014 
(OPHTHALMOLOGICAL SERVICES: MEDICAL EXAMINATION AND 
EVALUATION, WITH INITIATION OR CONTINUATION OF 
DIAGNOSTIC AND TREATMENT PROGRAM), 92018 
(OPHTHALMOLOGICAL EXAMINATION AND EVALUATION, 
UNDER GENERAL ANESTHESIA, WITH OR WITHOUT 
MANIPULATION OF GLOBE FOR PASSIVE RANGE OF MOTION), 
92019 (OPHTHALMOLOGICAL EXAMINATION AND EVALUATION, 
UNDER GENERAL ANESTHESIA, WITH OR WITHOUT 
MANIPULATION OF GLOBE FOR PASSIVE RANGE OF MOTION), 
92225 (OPHTHALMOSCOPY, EXTENDED, WITH RETINAL DRAWING 
(EG, FOR RETINAL DETACHMENT, MELANOMA), WITH 
INTERPRETATION AND REPORT), 92226 (OPHTHALMOSCOPY,
EXTENDED, WITH RETINAL DRAWING (EG, FOR RETINAL 
DETACHMENT, MELANOMA), WITH INTERPRETATION AND 
REPORT), 92230 (FLUORESCEIN ANGIOSCOPY WITH 
INTERPRETATION AND REPORT), 92235 (FLUORESCEIN 
ANGIOGRAPHY (INCLUDES MULTIFRAME IMAGING) WITH 
INTERPRETATION AND REPORT), 92240 (INDOCYANINE-GREEN 
ANGIOGRAPHY (INCLUDES MULTIFRAME IMAGING) WITH),  92250 
(FUNDUS PHOTOGRAPHY WITH INTERPRETATION AND REPORT), 

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92260 (OPHTHALMODYNAMOMETRY), V72.0 (EXAMINATION OF 
EYES AND VISION)
HCPCS: S0620 (ROUTINE OPHTHALMOLOGICAL EXAMINATION 
INCLUDING REFRACTION; NEW PATIENT), S0621 (ROUTINE 
OPHTHALMOLOGICAL EXAMINATION INCLUDING REFRACTION; 
ESTABLISHED PATIENT), S0625 (RETINAL TELESCREENING BY 
DIGITAL IMAGING OF MULTIPLE DIFFERENT FUND US AREAS TO 
SCREEN FOR VISION-THREATENING CONDITIONS, INCLUDING 
IMAGING, INTERPRETATION AND REPORT), S3000 (DIABETIC 
INDICATOR; RETINAL EYE EXAM, DILATED, BILATERAL)
Diabetes with ophthalmic manifestations
250.5x
Glaucoma
365.xx
Cataract
366.xx, 743.30-743.34 (CONGENITAL CATARACT: CAPSULAR AND 
SUBCAPSULAR, CORTICAL AND ZONULAR, NUCLEAR, TOTAL 
AND SUBTOTAL)
Retinal detachment, vitreous hemorrhage, vitrectomy
ICD-9-CM Diagnosis 361.9x, 379.23 
ICD-9-CM procedure 14.7x (OPERATIONS ON VITREOUS)
Pyelonephritis/infections of kidney
590.xx
Diabetic neuropathy
250.6 (DIABETES WITH NEUROLOGICAL MANIFESTATIONS), 357.2 
(POLYNEUROPATHY IN DIABETES)
Mononeuropathy or polyneuropathy
354.xx (MONONEURITIS OF UPPER LIMB AND MONONEURITIS 
MULTIPLEX)
355.xx (MONONEURITIS OF LOWER LIMB AND UNSPECIFIED SITE)
356.xx HEREDITARY AND IDIOPATHIC PERIPHERAL 
NEUROPATHY)
357.xx (INFLAMMATORY AND TOXIC NEUROPATHY)
Peripheral autonomic neuropathy
337.1x
Gastroparesis
536.3
Peripheral vascular disease or PVD surgery
1 inpatient or 2 outpatient claims with any of the following codes:
ICD9 diagnosis:
440.20 - 440.24 (ATHEROSCLEROSIS OF NATIVE ARTERIES OF THE 
EXTREMITIES, ATHEROSCLEROSIS OF NATIVE ARTERIES OF THE 
EXTREMITIES WITH INTERMITTENT CLAUDICATION, 
ATHEROSCLEROSIS OF NATIVE ARTERIES OF THE EXTREMITIES 
WITH REST PAIN, ATHEROSCLEROSIS OF NATIVE ARTERIES OF 
THE EXTREMITIES WITH ULCERATION, ATHEROSCLEROSIS OF 
NATIVE ARTERIES OF THE EXTREMITIES WITH GANGRENE), 
440.29 – 440.32 (OTHER ATHEROSCLEROSIS OF NATIVE ARTERIES 
OF THE EXTREMITIES, ATHEROSCLEROSIS OF BYPASS GRAFT OF 
THE EXTREMITIES, ATHEROSCLEROSIS OF AUTOLOGOUS VEIN 
BYPASS GRAFT OF THE EXTREMITIES, ATHEROSCLEROSIS OF 
NONAUTOLOGOUS BIOLOGICAL BYPASS GRAFT OF THE 
EXTREMITIES), 440.3 (ATHEROSCLEROSIS OF BYPASS GRAFT OF 
THE EXTREMITIES), 443.9 (PERIPHERAL VASCULAR DISEASE 
UNSPECIFIED) 
ICD9 procedure:
38.08 (INCISION OF VESSELS, LOWER LIMB ARTERIES), 38.09 
(INCISION OF VESSELS, LOWER LIMB VEINS), 38.18 
(ENDARTERECTOMY, LOWER LIMB ARTERIES), 38.48 (RESECTION 
OF VESSEL WITH REPLACEMENT, LOWER LIMB ARTERIES), 38.49 
(RESECTION OF VESSEL WITH REPLACEMENT, LOWER LIMB 
VEINS), 39.25 (AORTA-ILIAC-FEMORAL BYPASS), 39.5 (OTHER 
REPAIR OF VESSELS), 39.9 (OTHER OPERATIONS ON VESSELS), 
84.10 - 84.17 (AMPUTATION OF LOWER LIMB, AMPUTATION OF 
TOE, AMPUTATION THROUGH FOOT, DISARTICULATION OF 
ANKLE, AMPUTATION OF ANKLE THROUGH MALLEOLI OF TIBIA 
AND FIBULA, OTHER AMPUTATION BELOW KNEE, 
DISARTICULATION OF KNEE, AMPUTATION ABOVE KNEE)
HCPCs:
35256 (REPAIR BLOOD VESSEL WITH VEIN GRAFT; LOWER 
EXTREMITY), 35286 (REPAIR BLOOD VESSEL WITH GRAFT OTHER 
THAN VEIN; LOWER EXTREMITY), 35351 
(THROMBOENDARTERECTOMY, INCLUDING PATCH GRAFT, IF 
PERFORMED; ILIAC), 35355 (THROMBOENDARTERECTOMY, 
INCLUDING PATCH GRAFT, IF PERFORMED; ILIOFEMORAL), 35361 
(THROMBOENDARTERECTOMY, INCLUDING PATCH GRAFT, IF 
PERFORMED; COMBINED AORTOILIAC), 35363 
(THROMBOENDARTERECTOMY, INCLUDING PATCH GRAFT, IF 
PERFORMED; COMBINED AORTOILIOFEMORAL), 35371 

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(THROMBOENDARTERECTOMY, INCLUDING PATCH GRAFT, IF 
PERFORMED; COMMON FEMORAL), 35372 
(THROMBOENDARTERECTOMY, INCLUDING PATCH GRAFT, IF 
PERFORMED; DEEP (PROFUNDA) FEMORAL), 35381 
(THROMBOENDARTERECTOMY, W/WO PATCH GRAFT; 
FEMORAL/POPLITEAL/TIBIOPERONEAL), 35454  (TRANSLUMINAL 
BALLOON ANGIOPLASTY, OPEN; ILIAC), 35456 (TRANSLUMINAL 
BALLOON ANGIOPLASTY, OPEN; FEMORAL-POPLITEAL), 35459 
(TRANSLUMINAL BALLOON ANGIOPLASTY, OPEN; 
TIBIOPERONEAL TRUNK & BRANCHES), 35470 (TRANSLUMINAL 
BALLOON ANGIOPLASTY, PERCUTANEOUS; TIBIOPERONEAL 
TRUNK/BRANCHES, EACH VESSEL), 35473 (TRANSLUMINAL 
BALLOON ANGIOPLASTY, PERCUTANEOUS; ILIAC), 35474 
(TRANSLUMINAL BALLOON ANGIOPLASTY, PERCUTANEOUS; 
FEMORAL-POPLITEAL), 35482 (TRANSLUMINAL PERIPHERAL 
ATHERECTOMY, OPEN; ILIAC), 35483 (TRANSLUMINAL 
PERIPHERAL ATHERECTOMY, OPEN; FEMORAL-POPLITEAL), 
35485 (TRANSLUMINAL PERIPHERAL ATHERECTOMY, OPEN; 
TIBIOPERONEAL TRUNK & BRANCHES), 35492 (TRANSLUMINAL 
PERIPHERAL ATHERECTOMY, PERCUTANEOUS; ILIAC), 35493 
(TRANSLUMINAL PERIPHERAL ATHERECTOMY, PERCUTANEOUS; 
FEMORAL-POPLITEAL), 35495 (TRANSLUMINAL PERIPHERAL 
ATHERECTOMY, PERCUTANEOUS; TIBIOPERONEAL TRUNK & 
BRANCHES), 35521 (BYPASS GRAFT, WITH VEIN; AXILLARY-
FEMORAL), 35533 (BYPASS GRAFT, WITH VEIN; AXILLARY-
FEMORAL-FEMORAL), 35541 (BYPASS GRAFT, W/VEIN; 
AORTOILIAC/BI-ILIAC), 35546 (BYPASS GRAFT, W/VEIN; 
AORTOFEMORAL/BIFEMORAL), 35548 (BYPASS GRAFT, W/VEIN; 
AORTOILIOFEMORAL, UNILAT), 35549 (BYPASS GRAFT, W/VEIN; 
AORTOILIOFEMORAL, BILAT), 35551 (BYPASS GRAFT, W/VEIN; 
AORTOFEMORAL-POPLITEAL), 35556 (BYPASS GRAFT, WITH VEIN; 
FEMORAL-POPLITEAL), 35558 (BYPASS GRAFT, WITH VEIN; 
FEMORAL-FEMORAL), 35563 (BYPASS GRAFT, WITH VEIN; 
ILIOILIAC), 35565 (BYPASS GRAFT, WITH VEIN; ILIOFEMORAL), 
35566 (BYPASS GRAFT, WITH VEIN; FEMORAL-ANTERIOR TIBIAL, 
POSTERIOR TIBIAL, PERONEAL ARTERY OR OTHER DISTAL 
VESSELS), 35571 (BYPASS GRAFT, WITH VEIN; POPLITEAL-TIBIAL, 
-PERONEAL ARTERY OR OTHER DISTAL VESSELS), 35621 (BYPASS 
GRAFT, WITH OTHER THAN VEIN; AXILLARY-FEMORAL),  35623 
(BYPASS GRAFT, WITH OTHER THAN VEIN; AXILLARY-
POPLITEAL OR –TIBIAL), 35641 (BYPASS GRAFT, W/OTHER THAN 
VEIN; AORTOILIAC/BI-ILIAC), 35646 (BYPASS GRAFT, WITH OTHER 
THAN VEIN; AORTOBIFEMORAL), 35647 (BYPASS GRAFT, WITH 
OTHER THAN VEIN; AORTOFEMORAL),35650 (BYPASS GRAFT, 
WITH OTHER THAN VEIN; AXILLARY-AXILLARY), 35651 (BYPASS 
GRAFT, W/OTHER THAN VEIN; AORTOFEMORAL-POPLITEAL), 
35654 (BYPASS GRAFT, WITH OTHER THAN VEIN; AXILLARY-
FEMORAL-FEMORAL), 35656 (BYPASS GRAFT, WITH OTHER THAN 
VEIN; FEMORAL-POPLITEAL), 35661 (BYPASS GRAFT, WITH 
OTHER THAN VEIN; FEMORAL-FEMORAL), 35663 (BYPASS GRAFT, 
WITH OTHER THAN VEIN; ILIOILIAC), 35666 (BYPASS GRAFT, 
WITH OTHER THAN VEIN; FEMORAL-ANTERIOR TIBIAL, 
POSTERIOR TIBIAL, OR PERONEAL ARTERY), 35671 (BYPASS 
GRAFT, WITH OTHER THAN VEIN; POPLITEAL-TIBIAL OR -
PERONEAL ARTERY), 27590 (AMPUTATION, THIGH, THROUGH 
FEMUR, ANY LEVEL), 27591 (AMPUTATION, THIGH, THROUGH 
FEMUR, ANY LEVEL; IMMEDIATE FITTING TECHNIQUE 
INCLUDING FIRST CAST), 27592 (AMPUTATION, THIGH, THROUGH 
FEMUR, ANY LEVEL; OPEN, CIRCULAR (GUILLOTINE)), 27594 
(AMPUTATION, THIGH, THROUGH FEMUR, ANY LEVEL; 
SECONDARY CLOSURE OR SCAR REVISION), 27596 (AMPUTATION, 
THIGH, THROUGH FEMUR, ANY LEVEL; RE-AMPUTATION), 27880 
(AMPUTATION, LEG, THROUGH TIBIA AND FIBULA), 27881 
(AMPUTATION, LEG, THROUGH TIBIA AND FIBULA; WITH 
IMMEDIATE FITTING TECHNIQUE INCLUDING APPLICATION OF 
FIRST CAST), 27882 (AMPUTATION, LEG, THROUGH TIBIA AND 
FIBULA; OPEN, CIRCULAR (GUILLOTINE)), 27884 (AMPUTATION, 
LEG, THROUGH TIBIA AND FIBULA; SECONDARY CLOSURE OR 
SCAR REVISION), 27886 (AMPUTATION, LEG, THROUGH TIBIA AND 
FIBULA; RE-AMPUTATION), 27888 (AMPUTATION, ANKLE, 
THROUGH MALLEOLI OF TIBIA AND FIBULA (EG, SYME, 
PIROGOFF TYPE PROCEDURES), WITH PLASTIC CLOSURE AND 
RESECTION OF NERVES)       
Deep vein thrombosis and venous embolism
451.1 (PHLEBITIS AND THROMBOPHLEBITIS OF DEEP VEINS OF 

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LOWER EXTREMITIES), 451.2 (PHLEBITIS AND 
THROMBOPHLEBITIS OF LOWER EXTREMITIES UNSPECIFIED), 
451.81 (PHLEBITIS AND THROMBOPHLEBITIS OF ILIAC VEIN), 451.9 
(PHLEBITIS AND THROMBOPHLEBITIS OF UNSPECIFIED SITE), 
453.1 (THROMBOPHLEBITIS MIGRANS), 453.2 (EMBOLISM AND 
THROMBOSIS OF INFERIOR VENA CAVA), 453.8 (ACUTE VENOUS 
EMBOLISM AND THROMBOSIS OF OTHER SPECIFIED VEINS), 453.9 
(EMBOLISM AND THROMBOSIS OF UNSPECIFIED SITE), 415.1x 
(pulmonary embolism)
Diabetes with peripheral circulatory disorders
250.7 Diabetes with peripheral circulatory disorders
Coronary atherosclerosis
414.0x
Atherosclerosis
ICD-9 440.9 (arteriosclerosis)
ICD-9 429.2 (ASCVD)
Aortic aneurysm and dissection
441.xx
Other aneurysm of artery of lower extremity
442.3
Atherosclerosis of extremity with ulceration
440.23
Peripheral vascular disease
443.9 
Arterial embolism and thrombosis of lower 
extremity
444.22 
Peripheral angiopathy
443.81 
Gangrene 
785.4x
Diabetic foot
707.1x (ulcer of lower limbs)
Amputation 
ICD-9 diagnosis: V49.7x – lower limb amputation status, V52.1 –
artificial leg
ICD-9 procedure: 84.1x (amputation of lower limb)
CPT: 26910 (AMPUTATION, METACARPAL, WITH FINGER OR 
THUMB (RAY AMPUTATION), SINGLE, WITH OR WITHOUT 
INTEROSSEOUS TRANSFER), 27290 (INTERPELVIABDOMINAL 
AMPUTATION (HINDQUARTER AMPUTATION), 27295 
(DISARTICULATION OF HIP), 27590 – 27598 (AMPUTATION, THIGH, 
THROUGH FEMUR, ANY LEVEL; AMPUTATION, THIGH, THROUGH 
FEMUR, ANY LEVEL; IMMEDIATE FITTING TECHNIQUE; 
AMPUTATION, THIGH, THROUGH FEMUR, ANY LEVEL; OPEN, 
CIRCULAR (GUILLOTINE); AMPUTATION, THIGH, THROUGH 
FEMUR, ANY LEVEL; SECONDARY CLOSURE OR SCAR REVISION; 
AMPUTATION, THIGH, THROUGH FEMUR, ANY LEVEL; RE-
AMPUTATION; DISARTICULATION AT KNEE), 27880-27889 
(AMPUTATION, LEG, THROUGH TIBIA AND FIBULA; 
AMPUTATION, LEG, THROUGH TIBIA AND FIBULA; WITH 
IMMEDIATE FITTING TECHNIQUE INCLUDING APPLICATION OF 
FIRST CAST; AMPUTATION, LEG, THROUGH TIBIA AND FIBULA; 
OPEN, CIRCULAR (GUILLOTINE); AMPUTATION, LEG, THROUGH 
TIBIA AND FIBULA; SECONDARY CLOSURE OR SCAR REVISION; 
AMPUTATION, LEG, THROUGH TIBIA AND FIBULA; RE-
AMPUTATION; AMPUTATION, ANKLE, THROUGH MALLEOLI OF 
TIBIA AND FIBULA (EG, SYME, PIROGOFF TYPE PROCEDURES), 
WITH PLASTIC CLOSURE AND RESECTION OF NERVES; ANKLE 
DISARTICULATION), 28800 (AMPUTATION, FOOT; MIDTARSAL (EG, 
CHOPART TYPE PROCEDURE)), 28805 (AMPUTATION, FOOT; 
TRANSMETATARSAL), 28810 (AMPUTATION, METATARSAL, WITH 
TOE, SINGLE), 28820 (AMPUTATION, TOE; 
METATARSOPHALANGEAL JOINT), 28825 (AMPUTATION, TOE; 
INTERPHALANGEAL JOINT)
(CPT-4 codes): 26910 (AMPUTATION, METACARPAL, WITH FINGER 
OR THUMB (RAY AMPUTATION), SINGLE, WITH OR WITHOUT 
INTEROSSEOUS TRANSFER)
Osteomyelitis
730.xx
Osteoporosis 
733.0x or the use of bisphosphonates (see below for definition), calcitonin, 
raloxifene, or
teriparatide
Skin infections
680.xx-686.xx (CARBUNCLE AND FURUNCLE, CELLULITIS AND 
ABSCESS OF FINGER AND TOE, CELLULITIS AND ABSCESS OF 
FINGER AND TOE, ACUTE LYMPHADENITIS, IMPETIGO, 
PILONIDAL CYST, OTHER LOCAL INFECTIONS OF SKIN AND 
SUBCUTANEOUS TISSUE, UNSPECIFIED LOCAL INFECTION OF 
SKIN AND SUBCUTANEOUS TISSUE)
Skin ulcer
682.xx
Chronic ulcer of skin
707.xx
Diabetes with other specified manifestations 
250.8x

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Diabetes with unspecified complication
250.9x
Diabetic bone changes 
731.8x
Erectile dysfunction
607.84 
Nutrition counseling
CPT-4 code:
97802 – 97804 (MEDICAL NUTRITION THERAPY; INITIAL 
ASSESSMENT AND INTERVENTION, INDIVIDUAL, FACE-TO-FACE 
WITH THE PATIENT, EACH 15 MINUTES; MEDICAL NUTRITION 
THERAPY; RE-ASSESSMENT AND INTERVENTION, INDIVIDUAL, 
MEDICAL NUTRITION THERAPY; RE-ASSESSMENT AND 
INTERVENTION, INDIVIDUAL; MEDICAL NUTRITION THERAPY; 
GROUP (2 OR MORE INDIVIDUAL(S)), EACH 30 MINUTES)
S9470 (NUTRITIONAL COUNSELING, DIETITIAN VISIT)
G0270 – G0271 (MEDICAL NUTRITION THERAPY; REASSESSMENT 
AND SUBSEQUENT INTERVENTION(S) FOLLOWING SECOND 
REFERRAL IN SAME YEAR FOR CHANGE IN DIAGNOSIS, MEDICAL 
CONDITION OR TREATMENT REGIMEN (INCLUDING ADDITIONAL 
HOURS NEEDED FOR RENAL DISEASE), INDIVIDUAL, FACE TO 
FACE WITH THE PATIENT, EACH 15 MINUTES  - OR - GROUP (2 OR 
MORE INDIVIDUALS), EACH 30 MINUTES)
Diabetes education
CPT-4:
98960 – 98960 (EDUCATION AND TRAINING FOR PATIENT SELF-
MANAGEMENT BY A QUALIFIED, NONPHYSICIAN HEALTH CARE 
PROFESSIONAL USING A STANDARDIZED CURRICULUM)
G0108 – G0109 (DIABETES OUTPATIENT SELF-MANAGEMENT 
TRAINING SERVICES, INDIVIDUAL, PER 30 MINUTES; DIABETES 
OUTPATIENT SELF-MANAGEMENT TRAINING SERVICES, GROUP
SESSION (2 OR MORE), PER 30 MINUTES)
Podiatry
CPT-4:
11055 (PARING OR CUTTING OF BENIGN HYPERKERATOTIC 
LESION (EG, CORN OR CALLUS); SINGLE LESION), 11056 (2 TO 4 
LESIONS), 11057 (MORE THAN 4 LESIONS), 11719 (TRIMMING OF 
NONDYSTROPHIC NAILS, ANY NUMBER), G0127 (TRIMMING OF 
DYSTROPHIC NAILS, ANY NUMBER), 11720 – 11721 (DEBRIDEMENT 
OF NAIL(S) BY ANY METHOD(S); 1 TO 5; 6 OR MORE)
G0245 (INITIAL PHYSICIAN EVALUATION AND MANAGEMENT OF 
A DIABETIC PATIENT WITH DIABETIC SENSORY NEUROPATHY 
RESULTING IN A LOSS OF PROTECTIVE SENSATION (LOPS) WHICH 
MUST INCLUDE: (1) THE DIAGNOSIS OF LOPS, (2) A PATIENT 
HISTORY, (3) A PHYSICAL EXAMINATION THAT CONSISTS OF AT 
LEAST THE FOLLOWING ELEMENTS: (A) VISUAL INSPECTION OF 
THE FOREFOOT, HINDFOOT AND TOE WEB SPACES, 
(B)EVALUATION OF A PROTECTIVE SENSATION, (C) EVALUATION 
OF FOOT STRUCTURE AND BIOMECHANICS, (D) EVALUATION OF 
VASCULAR STATUS AND SKIN INTEGRITY, AND (E) EVALUATION 
AND RECOMMENDATION OF FOOTWEAR AND (4) PATIENT 
EDUCATION), G0246 (FOLLOW-UP EVALUATION)
Urinary tract infection
599.0x
Renal Dysfunction
Acute renal disease (see below)
Chronic renal disease (see below)
Diabetic nephropathy (see below)
Hypertensive nephropathy (see below)
Miscellaneous Renal Insufficiency (see below)
or
ICD-9 procedure:
39.95 hemodialysis
54.98 peritoneal dialysis
V56.0 extracorporeal dialysis
V56.8 peritoneal dialysis
CPT-4: 90935 – 90993 (hemodialysis, miscellaneous dialysis procedures, see 
code appendix), 99512 (home visit for hemodialysis), 99559 (home infusion, 
peritoneal dialysis, per visit)
Acute Renal Disease
580.0 (ACUTE GLOMERULONEPHRITIS), 580.4 (ACUTE 
GLOMERULONEPHRITIS WITH LESION OF RAPIDLY PROGRESSIVE 
GLOMERULONEPHRITIS), 580.8 (WITH OTHER SPECIFIED 
PATHOLOGICAL LESION INKIDNEY), 580.9 (WITH UNSPECIFIED 
PATHOLOGICAL LESION IN KIDNEY), 581.0 (NEPHROTIC 
SYNDROME WITH LESION OF MEMBRANOUS 
GLOMERULONEPHRITIS), 581.1 (WITH LESION OF MEMBRANOUS 

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GLOMERULONEPHRITIS), 581.2 (NEPHROTIC SYNDROME WITH 
LESION OF MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS), 
581.3 (NEPHROTIC SYNDROME WITH LESION OF MINIMAL 
CHANGE GLOMERULONEPHRITIS), 581.8 (NEPHROTIC SYNDROME 
WITH OTHER SPECIFIED PATHOLOGICAL LESION IN KIDNEY), 
581.9 (NEPHROTIC SYNDROME WITH UNSPECIFIED 
PATHOLOGICAL LESION IN KIDNEY), 584.6 (ACUTE KIDNEY 
FAILURE WITH LESION OF RENAL CORTICAL NECROSIS), 584.7 
(ACUTE KIDNEY FAILURE WITH LESION OF RENAL MEDULLARY 
[PAPILLARY] NECROSIS), 584.8 (ACUTE KIDNEY FAILURE WITH 
OTHER SPECIFIED PATHOLOGICAL LESION IN KIDNEY), 584.9 
(ACUTE KIDNEY FAILURE, UNSPECIFIED)
Chronic Renal Insufficiency
582.x (CHRONIC GLOMERULONEPHRITIS), 583.x (NEPHRITIS AND 
NEPHROPATHY NOT SPECIFIED AS ACUTE OR CHRONIC), 585.x 
(CHRONIC KIDNEY DISEASE (CKD)), 586.x (RENAL FAILURE 
UNSPECIFIED), 587.x (RENAL SCLEROSIS UNSPECIFIED)
Diabetic Nephropathy
250.4 (DIABETES WITH RENAL MANIFESTATIONS), 250.41 
(DIABETES MELLITUS WITH RENAL MANIFESTATIONS TYPE I 
NOT STATED AS UNCONTROLLED), 250.42 (DIABETES MELLITUS 
WITH RENAL MANIFESTATIONS TYPE II OR UNSPECIFIED TYPE 
UNCONTROLLED), 250.43 (DIABETES MELLITUS WITH RENAL 
MANIFESTATIONS TYPE I UNCONTROLLED)
Hypertensive Nephropathy
403.xx (HYPERTENSIVE CHRONIC KIDNEY DISEASE), 404.xx 
(HYPERTENSIVE HEART AND CHRONIC KIDNEY DISEASE)
Miscellaneous Renal Insufficiency
274.10 (GOUTY NEPHROPATHY), 440.1 (ATHEROSCLEROSIS OF 
RENAL ARTERY), 442.1 (ANEURYSM OF RENAL ARTERY), 453.3 
(EMBOLISM AND THROMBOSIS OF RENAL VEIN), 581.xx 
(NEPHROTIC SYNDROME), 593.xx (OTHER DISORDERS OF KIDNEY 
AND URETER), 753.0 (CONGENITAL ANOMALIES OF URINARY 
SYSTEM), 753.3 (OTHER SPECIFIED ANOMALIES OF KIDNEY), 
866.00 (INJURY TO KIDNEY ), 866.01 (HEMATOMA OF KIDNEY 
WITHOUT RUPTURE OF CAPSULE WITHOUT OPEN WOUND INTO 
CAVITY), 866.1 (INJURY TO KIDNEY WITH OPEN WOUND INTO 
CAVITY)
Prior chronic liver disease and cirrhosis
571.xx
Prior other liver disease
ICD-9 diagnosis:
070.xx viral hepatitis
570.xx acute and subacute necrosis of liver
572.xx liver abscess and sequalae of chronic liver disease
573.xx other disorders of liver
456.0x – 456.2x esophageal varices
155.0x primary cancer of liver
155.1x cancer of intrahepatic bile ducts
155.2x cancer of liver not specified as primary or secondary
576.8x cholestasis
782.4x Jaundice
789.5x Ascites
ICD-9 procedure codes:
39.1x intra-abdominal venous shunt
42.91 ligation of esophageal varices
Porphyria
277.1x (DISORDERS OF PORPHYRIN METABOLISM)
Hypertension
1 inpatient or 2 outpatient claims with any of ICD-9 codes : 401.xx-405.xx 
(ESSENTIAL HYPERTENSION; HYPERTENSIVE HEART DISEASE; 
HYPERTENSIVE CHRONIC KIDNEY DISEASE; HYPERTENSIVE 
HEART AND CHRONIC KIDNEY DISEASE; SECONDARY 
HYPERTENSION)
Hyperlipidemia
272.xx [hospital discharge, any position or 2 outpatient visits]
Congestive heart failure
1 inpatient or 2 outpatient claims with any of ICD-9 codes : 428.xx (HEART 
FAILURE), 398.91 (RHEUMATIC HEART FAILURE (CONGESTIVE)), 
402.01 (MALIGNANT HYPERTENSIVE HEART DISEASE WITH 
HEART FAILURE), 402.11 (BENIGN HYPERTENSIVE HEART 
DISEASE WITH HEART FAILURE), 402.91 (UNSPECIFIED 
HYPERTENSIVE HEART DISEASE WITH HEART FAILURE), 404.01 
(HYPERTENSIVE HEART AND CHRONIC KIDNEY DISEASE, 
MALIGNANT, WITH HEART FAILURE AND WITH CHRONIC 
KIDNEY DISEASE STAGE I THROUGH STAGE IV, OR 
UNSPECIFIED), 404.11 (HYPERTENSIVE HEART AND CHRONIC 
KIDNEY DISEASE, BENIGN, WITH HEART FAILURE OR AND WITH 
CHRONIC KIDNEY DISEASE STAGE I THROUGH STAGE IV, OR 
UNSPECIFIED), 404.91 (HYPERTENSIVE HEART AND CHRONIC 
KIDNEY DISEASE, UNSPECIFIED, WITH HEART FAILURE AND 
WITH CHRONIC KIDNEY DISEASE STAGE I THROUGH STAGE IV, 

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OR UNSPECIFIED), 404.03 (HYPERTENSIVE HEART AND CHRONIC 
KIDNEY DISEASE, MALIGNANT, WITH HEART FAILURE AND WITH 
CHRONIC KIDNEY DISEASE STAGE V OR END STAGE RENAL 
DISEASE), 404.13 (HYPERTENSIVE HEART AND CHRONIC KIDNEY 
DISEASE, BENIGN, WITH HEART FAILURE AND CHRONIC KIDNEY 
DISEASE STAGE V OR END STAGE RENAL DISEASE), 404.93 
(HYPERTENSIVE HEART AND CHRONIC KIDNEY DISEASE, 
UNSPECIFIED, WITH HEART FAILURE AND CHRONIC KIDNEY 
DISEASE STAGE V OR END STAGE RENAL DISEASE)
Edema
782.3x
Acute MI
410.xx
Old MI
412.xx
Unstable angina
411.xx
Stable angina
413.xx
Other chronic ischemic heart disease
414.xx (except for 414.0x, coronary atherosclerosis)
CABG
36.1x (BYPASS ANASTOMOSIS FOR HEART 
REVASCULARIZATION), 36.2x (HEART REVASCULARIZATION BY 
ARTERIAL IMPLANT)
CPT4:
33510 – 33536 (CORONARY ARTERY BYPASS, VEIN ONLY; 
SINGLE/2/3/4/5/6 (OR MORE) CORONARY VENOUS GRAFT; 
CORONARY ARTERY BYPASS, USING VENOUS GRAFT(S) AND 
ARTERIAL GRAFT(S) SINGLE/2/3/4/5/6 (OR MORE) VEIN GRAFT; 
REOPERATION, CORONARY ARTERY BYPASS PROCEDURE OR 
VALVE PROCEDURE, MORE THAN 1 MONTH AFTER ORIGINAL 
OPERATION; CORONARY ARTERY BYPASS, USING ARTERIAL 
GRAFT(S); SINGLE/2/3/4 (OR MORE) ARTERIAL GRAFT), 33545 
(REPAIR OF POST-INFARCTIONVENTRICULAR SEPTAL DEFECT 
WITH OR WITHOUT MYOCARDIAL RESECTION), 33572 
(CORONARY ENDARTERECTOMY, OPEN, ANY METHOD, OF LEFT 
ANTERIOR DESCENDING, CIRCUMFLEX, OR RIGHT CORONARY 
ARTERY)
Transmyocardial revascularization
36.31 (OPEN CHEST TRANSMYOCARDIAL REVASCULARIZATION),
36.32 (Other transmyocardial revascularization), 36.33 (Endoscopic 
transmyocardial revascularization), 36.34 Percutaneous transmyocardial 
revascularization
CPT-4: 
33140 (TRANSMYOCARDIAL LASER REVASCULARIZATION, BY 
THORACOTOMY), 33141(TRANSMYOCARDIAL LASER 
REVASCULARIZATION, BY THORACOTOMY, PERFORMED AT 
THE TIME OF OTHER OPEN CARDIAC PROCEDURES)
PTCA or atherectomy
00.66 (EXCISION OF LINGUAL THYROID), 36.01 (SINGLE VESSEL 
PERCUTANEOUS TRANSLUMINAL CORONARY ANGIOPLASTY 
[PTCA] OR CORONARY ATHERECTOMY WITH MENTION OF 
THROMBOLYTIC AGENT), 36.02 (SINGLE VESSEL PERCUTANEOUS 
TRANSLUMINAL CORONARY ANGIOPLASTY [PTCA] OR 
CORONARY ATHERECTOMY WITHOUT MENTION OF 
THROMBOLYTIC AGENT) , 36.03 (OPEN CHEST CORONARY 
ARTERY ANGIOPLASTY), 36.05 (MULTIPLE VESSEL 
PERCUTANEOUS TRANSLUMINAL CORONARY ANGIOPLASTY 
[PTCA] OR CORONARY ATHERECTOMY PERFORMED DURING THE 
SAME OPERATION, WITH OR WITHOUT MENTION OF 
THROMBOLYTIC AGENT), 36.09 (OTHER REMOVAL OF CORONARY 
ARTERY OBSTRUCTION)
CPT4: 
92973 (PERCUTANEOUS TRANSLUMINAL CORONARY 
THROMBECTOMY (LIST SEPARATELY IN ADDITION TO CODE FOR 
PRIMARY PROCEDURE), 92982 (PERCUTANEOUS TRANSLUMINAL 
CORONARY BALLOON ANGIOPLASTY; SINGLE VESSEL), 92984 
(PERCUTANEOUS TRANSLUMINAL CORONARY BALLOON 
ANGIOPLASTY; EACH ADDITIONAL VESSEL), 92995 
(PERCUTANEOUS TRANSLUMINAL CORONARY ATHERECTOMY, 
BY MECHANICAL OR OTHER METHOD, WITH OR WITHOUT 
BALLOON ANGIOPLASTY; SINGLE VESSEL), 92996 (EACH 
ADDITIONAL VESSEL), 92920 – 92921, 92924 – 92925, 92937, 92938, 
92941, 92943, 92944
Stent
36.06 (bare metal)
36.07 (drug-eluting)
CPT4:
92980, 92981, 92928 – 92929, 92933 - 92934
CABG or PTCA or atherectomy or Stent
See above for definition

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History of PTCA
V45.82
History of CABG
V45.81
History of PTCA or History of CABG
See above for definition
Injection/infusion of thrombolytic agent (Alteplase, 
Anistreplase, Reteplase, Streptokinase, Tenecteplase, 
Tissue plasminogen activator, Urokinase)
99.10
Rheumatic/aortic/mitral valve disease
394.xx (DISEASES OF MITRAL VALVE), 395.xx (DISEASES OF 
AORTIC VALVE), 396.xx (DISEASES OF MITRAL AND AORTIC 
VALVES), 424.0x (MITRAL VALVE DISORDERS), 424.1x (AORTIC 
VALVE DISORDERS)
Other cardiovascular disorders
390.xx-393.xx, 397.xx, 398.xx, 420.xx-424.xx (except for 424.0x, 424.1x), 
425.xx, 441.xx-447.xx (except for 443.9x, 745.xx-747.xx)
Cardiac dysrhythmia
427.xx, exclude 427.5 (cardiac arrest)
Atrial fibrillation or flutter
427.3x
Ventricular fibrillation or flutter 
427.4x
Other dysrythmias
427.0x (PAROXYSMAL SUPRAVENTRICULAR TACHYCARDIA), 
427.1x (PAROXYSMAL VENTRICULAR TACHYCARDIA), 427.2x 
(PAROXYSMAL TACHYCARDIA UNSPECIFIED), 427.6x 
(PREMATURE BEATS), 427.8x (OTHER SPECIFIED CARDIAC 
DYSRHYTHMIAS), 427.9x (CARDIAC DYSRHYTHMIA 
UNSPECIFIED), 785.0x (TACHYCARDIA UNSPECIFIED)
Cardiac conduction disorders
426.xx
History of sudden cardiac arrest
V12.53
Ischemic stroke
433.x1 (OCCLUSION AND STENOSIS CAROTID ARTERIES), 434.x1 
(CEREBRAL EMBOLISM), 436.xx (ACUTE BUT ILL-DEFINED 
CEREBROVASCULAR DISEASE), 437.1x (OTHER GENERALIZED 
ISCHEMIC CEREBROVASCULAR DISEASE), 437.9x (UNSPECIFIED 
CEREBROVASCULAR DISEASE)
Late effects of cerebrovascular disease
438.xx
TIA
435.xx
Personal history of stroke
V12.54
Hemorrhagic stroke
430.xx (SUBARACHNOID HEMORRHAGE), 431.xx (INTRACEREBRAL 
HEMORRHAGE), 432.xx (OTHER AND UNSPECIFIED 
INTRACRANIAL HEMORRHAGE)
COPD
491.xx (CHRONIC BRONCHITIS), 492.xx (EMPHYSEMA), 496.xx 
(CHRONIC AIRWAY OBSTRUCTION NOT ELSEWHERE 
CLASSIFIED), 493.2x (chronic obstructive asthma)
Asthma
493.xx (excluding 493.2x)
Obstructive sleep apnea
327.23
Oxygen 
V46.2x
Pneumonia
480.xx – 486.xx, 487.0x, 507.xx
Polyuria, Nocturia
788.4
Polydipsia
783.5
Acidosis
276.2, diabetic acidosis (249.1, 250.1)
Asthenia/fatigue
780.79
Syncope and collapse
780.2
Abdominal pain
789.0x
Nausea and/or vomiting
787.0x
Diarrhea
787.91
Pancreatitis
577.0 (DISEASES OF PANCREAS), 577.1 (CHRONIC PANCREATITIS)
Hyperthyroidism
242.1x (TOXIC UNINODULAR GOITER), 242.3x (TOXIC NODULAR 
GOITER UNSPECIFIED TYPE), 242.9x (THYROTOXICOSIS WITHOUT 
MENTION OF GOITER OR OTHER CAUSE)
Hypothyroidism
243 (CONGENITAL HYPOTHYROIDISM), 244.x (ACQUIRED 
HYPOTHYROIDISM)
Other disorders of thyroid gland
240.xx – 246.xx, excluding hyperthyroidism and hypothyroidism 
(SIMPLE AND UNSPECIFIED GOITER; NONTOXIC NODULAR 
GOITER; THYROIDITIS; OTHER DISORDERS OF THYROID)
Osteoarthritis
715.xx
Rheumatoid arthritis
714.xx
Other arthritis, arthropathies and musculoskeletal pain
710.xx−713.xx, 716.xx −719.xx, 725.xx−729.xx
Fractures
733.1x (PATHOLOGIC FRACTURE), 800.xx-829.xx (FRACTURE OF 
VAULT OF SKULL; FRACTURE OF BASE OF SKULL; FRACTURE OF 
FACE BONES; OTHER AND UNQUALIFIED SKULL FRACTURES; 
MULTIPLE FRACTURES INVOLVING SKULL OR FACE WITH OTHER 
BONES; FRACTURE OF VERTEBRAL COLUMN WITHOUT MENTION 
OF SPINAL CORD INJURY; FRACTURE OF VERTEBRAL COLUMN 
WITH SPINAL CORD INJURY; FRACTURE OF RIB(S) STERNUM 
LARYNX AND TRACHEA; FRACTURE OF PELVIS; ILL-DEFINED 
FRACTURES OF BONES OF TRUNK; FRACTURE OF CLAVICLE; 
FRACTURE OF SCAPULA; FRACTURE OF HUMERUS; FRACTURE 

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OF RADIUS AND ULNA; FRACTURE OF CARPAL BONE(S); 
FRACTURE OF METACARPAL BONE(S); FRACTURE OF ONE OR 
MORE PHALANGES OF HAND; MULTIPLE FRACTURES OF HAND 
BONES; ILL-DEFINED FRACTURES OF UPPER LIMB; MULTIPLE 
FRACTURES INVOLVING BOTH UPPER LIMBS AND UPPER LIMB 
WITH RIB(S) AND STERNUM; FRACTURE OF NECK OF FEMUR; 
FRACTURE OF OTHER AND UNSPECIFIED PARTS OF FEMUR; 
FRACTURE OF PATELLA; FRACTURE OF TIBIA AND FIBULA; 
FRACTURE OF ANKLE; FRACTURE OF ONE OR MORE TARSAL 
AND METATARSAL BONES; FRACTURE OF ONE OR MORE 
PHALANGES OF FOOT; OTHER MULTIPLE AND ILL-DEFINED 
FRACTURES OF LOWER LIMB; MULTIPLE FRACTURES INVOLVING 
BOTH LOWER LIMBS LOWER WITH UPPER LIMB AND LOWER 
LIMB(S) WITH RIB(S) AND STERNUM; FRACTURE OF UNSPECIFIED 
BONES)
Falls
E885 (ACCIDENTAL FALL ON SAME LEVEL FROM SLIPPING 
TRIPPING OR STUMBLING), E885.9x (ACCIDENTAL FALL FROM 
OTHER SLIPPING TRIPPING OR STUMBLING), E888.xx (OTHER AND 
UNSPECIFIED FALL)
Anemia
285.21 (ANEMIA IN CHRONIC KIDNEY DISEASE), 281.x (OTHER 
DEFICIENCY ANEMIAS)
Folate/vit-12 deficiency or vitamin B12 deficiency 
anemia
281.2 (FOLATE DEFICIENCY ANEMIA), 281.3 (OTHER SPECIFIED 
MEGALOBLASTIC ANEMIAS NOT ELSEWHERE CLASSIFIED)
Haemostatic disorders 
269.0x, 286.7x Vitamin K deficiency
286.0x-2x Hemophilia
286.3x Congenital afibrinogenemia 
286.4x Von Willebrand disease 
286.5x Hemorrhagic disorder due to intrinsic circulating anticoagulants
286.6x Disseminated intravascular coagulation 
286.9x Other and unspecified coagulation defects
287.1x Platelet defects
287.3x idiopathic thrombocytopenia
287.4x Secondary thrombocytopenia
287.5x Thrombocytopenia unspecified
289.81 Protein S deficiency, protein C deficiency
289.82 Secondary hypercoagulable state
289.84 Heparin-induced thrombocytopenia (HIT)
208.xx Leukemia
Convulsions or seizures NOS
345.xx (EPILEPSY), 780.39 (OTHER CONVULSIONS)
Parkinson’s disease
332.xx, 333.0x
Depression
293.83 (MOOD DISORDER IN CONDITIONS CLASSIFIED 
ELSEWHERE), 296.2x (MAJOR DEPRESSIVE DISORDER SINGLE 
EPISODE), 296.3x (MAJOR DEPRESSIVE DISORDER RECURRENT 
EPISODE), 296.90 (OTHER AND UNSPECIFIED EPISODIC MOOD 
DISORDER), 298.0x (DEPRESSIVE TYPE PSYCHOSIS), 300.4x 
(DYSTHYMIC DISORDER), 309.0x (ADJUSTMENT REACTION WITH 
ADJUSTMENT DISORDER WITH DEPRESSED MOOD), 309.1x 
(ADJUSTMENT REACTION WITH PROLONGED DEPRESSIVE 
REACTION), 309.28 (ADJUSTMENT DISORDER WITH MIXED 
ANXIETY AND DEPRESSED MOOD), 311 (DEPRESSIVE DISORDER 
NOT ELSEWHERE CLASSIFIED)
Bipolar disorder
296.0x, 296.1x, 296.4x, 296.5x, 296.6x, 296.7x, 296.8x, 296.99
Anxiety disorders
293.84, 300.0x, 300.2x, 300.3x, 309.24, 308.0x, 309.81 
Sleep disorder
307.4x, 327.0x, 327.2x 780.5x, 347.xx
Dementia
290.xx, 294.xx, 330.xx, 331.xx
Delirium
290.11, 290.3x, 290.41, 291.0x, 292.81, 293.xx, 348.3x, 349.82
Psychosis
290.8x, 290.9x, 295.xx, 297.xx, 298.xx, 299.xx, 780.1x
LIFE STYLE FACTORS
Alcohol abuse or dependence
291.xx (ALCOHOL-INDUCED MENTAL DISORDERS), 303.xx 
(ALCOHOL DEPENDENCE SYNDROME)
Drug abuse or dependence
292.xx (DRUG-INDUCED MENTAL DISORDERS), 304.xx (DRUG 
DEPENDENCE), 305.xx (NONDEPENDENT ABUSE OF DRUGS) 
(excluding 305.1x (NONDEPENDENT TOBACCO USE DISORDER))
Smoking 
V15.82 (PERSONAL HISTORY OF TOBACCO USE), 305.1x 
(NONDEPENDENT TOBACCO USE DISORDER), prescription of 
varenicline tartrate or nicotine replacement therapy
Obesity
278.00 (OVERWEIGHT, OBESITY AND OTHER 
HYPERALIMENTATION), 278.01 (MORBID OBESITY), V85.3x, V85.4x
Overweight
278.02

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Abnormal weight gain
783.1
MEDICATIONS
ACE inhibitor
Benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, 
quinapril, ramipril, trandolapril 
ARB
Azilsartan, candesartan, eprostartan, irbesartan, losartan, olmesartan, 
telmisartan, valsartan 
Beta blocker
Acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, 
labetalol, metoprolol tartrate, metoprolol succinate, propranolol, penbutolol, 
pindolol, nadolol, nebivolol, sotalol, timolol
Thiazides 
Bendroflumethiazide
Benzthiazide
Chlorothiazide
Chlorthalidone
Cyclothiazide
Hydrochlorothiazide
Hydroflumethiazide
Indapamide
Methyclothiazide
Metolazone
Polythiazide
Quinethazone
Trichlormethiazide
Loop diuretics
furosemide, bumetanide, torsemide, ethacrynic acid
Other diuretics
Amiloride, eplerenone, spironolactone, triamterene
Other antihypertensives
Doxazosin, eplerenone, prazosin, terazosin, clonidine, guanabenz, guanadrel, 
guanethidine, guanfacine, hydralazine, methyldopa, metyrosine, reserpine, 
minoxidil
Calcium channel blockers
Diltiazem 
Mibefradil 
Verapamil 
Amlodipine 
Clevidipine
Bepridil 
Felodipine
Isradipine
Nicardipine 
Nifedipine
Nimodipine
Nisoldipine
Amlodipine–atorvastatin
Nitrates
Nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, ranolazine
Aliskiren
Aliskiren
Digoxin
Digoxin
Antiarrhythmics
Amiodarone, dronedarone, flecainide, ibutilide, procainamide, propafenone, 
quinidine disopyramide, dofetilide, mexiletine, moricizine,
tocainide
Statins
Atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin, rosuvastatin, 
lovastatin–niacin, ezetimibe–simvastatin, pravastatin- aspirin, pitavastatin.
Other lipid-lowering drugs
Niacin
Nicotinic acid
Niacinamide
Fenofibrate
Gemfibrozil 
Cholestyramine 
Colesevelam 
Colestipol
Ezetimibe alone
Colesevelam 
Colesevelam
Bromocriptine 
Bromocriptine 
Pramlintide
Pramlintide
Oral anticoagulants
Warfarin, dabigatran, rivaroxaban, apixaban
Heparin and other LMWH
Heparin, dalteparin, enoxaparin, tinzaparin
Other anticoagulants
argatroban, bivalirudin, eptifibatide, fondaparinux, lepirudin, tirofiban
Aspirin
Aspirin alone
Antiplatelet
Clopidogrel, prasugrel, ticlopidine, aspirin–dipyridamole, dipyridamole 
alone, cilostazol, ticagrelor
Oral corticosteroids
Cortisone
hydrocortisone
prednisone
prednisolone
methylprednisolone

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triamcinolone
dexamethasone,
bethamethasone
Nonselective nonsteroidal anti-inflammatory drugs
diclofenac
etodolac
flurbiprofen
ketorolac
ibuprofen
indomethacin
meloxicam
naproxen
piroxicam
sulindac
Selective COX-2 inhibitors
Celecoxib
Rofecoxib
valdecoxib
Bisphosphonates
Alendronate, risedronate, ibandronate or etidronate, zoledronic acid, 
pamidronic acid 
DMARDs
Methotrexate, Hydroxychloroquine, Sulfasalazine, Leflunomide, 
Cyclosporine, Azathioprine, Cyclophosphamide, d-penicillamine Gold 
Sodium Thiomalate, Auranofin, Solganol, Myochrysine, Adalimumab, 
Etanercept, Infliximab, Certolizumab, Golimumab, Abatacept, Rituximab, 
Tocilizumab, Anakinra 
Opiates
Codeine
Fentanyl
Hydrocodone
Hydromorphone
Meperidine
Morphine
Oxycodone
Propoxyphene
Oxymorphone
Tramadol
Antidepressants
Paroxetine Citalopram Escitalopram Fluoxetine 
Fluvoxamine Sertraline Venlafaxine Desvenlafaxine
Levomilnacipran
Duloxetine Amitriptyline Amoxapine
Clomipramine Desipramine  Doxepin 
Imipramine Maprotiline Nortriptyline
Protriptyline Trimipramine Bupropion Mirtazapine 
Nefazodone Trazodone Phenelzine Isocarboxazid
Tranylcypropine Vilazodone, Vortioxetine
Antipsychotics
clozapine risperidone olanzapine                                                      
quetiapine aripiprazole ziprasidone  acetophenazine chlorpromazine                   
fluphenazine mesoridazine                                                    
perphenazine promazine                                                       
thioridazine trifluoperazine
triflupromazine chlorprothixene                                         
haloperidol loxapine molindone                                                       
pimozide thiothixene     asenapine iloperidone lurasidone paliperidone 
pimozide propiomazine triflupromazine                                                               
Anticonvulsants
carbamazepine, divalproex, eslicarbazepine, ethotoin,
ethosuximide, ezogabine, felbamate, fosphenytoin, gabapentin, lacosamide, 
lamotrigine, levetiracetam, mephenytoin, 
mephobarbital, methsuximide, oxcarbazepine, perampanel, phenobarbital, 
phenytoin, pregabalin, primidone, rufinamide, tiagabine, topiramate, valproic 
acid, vigabatrin, zonisamide
Lithium
lithium carbonate 
lithium citrate
Benzodiazepines
Alprazolam
Chlordiazepoxide
Clonazepam
Clorazepate 
Diazepam
Estazolam
Flurazepam 
Halazepam 
Lorazepam
Midazolam
Oxazepam
Prazepam
Quazepam
Temazepam

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Triazolam
Other anxiolytics/hypnotics
Eszopiclone
Zaleplon
Zolpidem 
Chloral hydrate
Diphenhydramine
Doxylamine
Ethclorvynol
Glutethimide
Methaqualone
buspirone
hydroxyzine 
meprobamate
Agents for dementia
Ergoloid 
donepezil 
rivastigmine
galantamine 
memantine
tacrine
Antiparkinson agents
Benztropine 
biperiden 
procyclidine 
trihexyphenidyl 
tolcapone 
amantadine 
levodopa
pergolide
pramixepole
ropinirole
rotigotine
carbidopa/levodopa
rasagiline 
selegiline
carbidopa

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ANNEX 3.3 GENERAL CONSIDERATIONS FOR DIABETES MELLITUS TYPE 2  
THERAPY
Insulin secretagogues, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, GLP-1 
receptor agonists, DPP-IV inhibitors, and insulin are approved for monotherapy of type 2 
DM.
Unless contraindicated, metformin is generally recommended as initial therapy because of its 
efficacy, known side-effect profile, and relatively low cost. Metformin has also the advantage 
that it promotes mild weight loss, lowers insulin levels, and improves the lipid profile slightly.
However, due to the paucity of long-term comparative effectiveness trials available, uniform 
recommendations on the best agent to be combined with metformin cannot be made. 
Advantages and disadvantages of specific drugs for each patient should be considered.

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Treatment algorithm for diabetes mellitus type 2 treatment
1st Use Agents
2nd Use Agents
If HbA1c > 7% after 2-3 months
3rd Use agents
If HbA1c > 7% after 
2-3 months
Metformin (added at, or
soon after, diagnosis)
If metformin is contraindicated1:
- sulfonylureas (Cheap, generally well-
tolerated)/meglitinides (considered in 
place of a sulfonylurea in patients with 
irregular meal schedules or with late 
postprandial hypoglycemia while on 
sulfonylurea agents)
- TZDs (No hypoglycemia)
- DPP-4 inhibitors (No weight gain, no 
hypoglycemia)
- GLP-1 receptor agonists where weight 
loss is seen as an essential aspect of 
therapy
- AGIs, colesevelam, bromocriptine, 
where available in selected patients, but 
their modest glycemic effects and side 
effect profiles make them less attractive 
candidates
Specific patient preferences, 
characteristics, susceptibilities to side 
effects, potential for weight gain and 
hypoglycaemia should play a major role 
in this drug selection
If markedly symptomatic patient and/or 
elevated blood glucose levels (FPG 
>11.1–13.9 mmol/L or 200–250 mg/dL) 
or HbA1C (>9.0%):
- Insulin with or without additional 
agents (starting with basal/intermediate 
insulin2 (insulin glargine, insulin 
detemir, or NPH insulin))
- sulfonylureas/meglitinides 
- TZDs 
- DPP-4 inhibitors
- GLP-1 receptor agonists 
- AGIs, colesevelam, bromocriptine 
(can be added but their modest 
glycemic effects and side effect 
profiles make them less attractive 
candidates)
No good evidence supports one 
combination therapy over another.
If markedly symptomatic patient and/or 
elevated blood glucose levels or 
HbA1C (>9%):
- basal insulin 
If already on basal insulin, 
intensification of insulin regimen with:
- addition of pre-meal rapid-acting 
insulin analogue
- twice daily pre-mixed insulin (fixed 
combination of an intermediate insulin 
with regular insulin or a rapid 
analogue)
Some studies have 
shown advantages of 
adding a third non-
insulin agent 
(sulfonylureas/meglitin
ides, TZDs, DPP-4 
inhibitors, GLP-1 
receptor agonists) to a 
two-drug combination 
that is not yet or no 
longer achieving the 
glycemic target.
However at this 
juncture, the most 
robust response will 
usually be with insulin, 
especially with 
elevated HbA1C 
(>9%). 
Metformin is often 
continued when basal 
insulin is added (less 
weight gain when the 
two are used together). 
Sulfonylureas/meglitini
des should be avoided 
once more complex 
insulin regimens than 
basal insulin are used.
TZDs should be 
reduced in dose (or 
stopped) to avoid 
edema and excessive 
weight gain (in certain 
individuals with large 
insulin requirements 
from severe insulin 
resistance, these 
insulin sensitizers may 
be very helpful in 
lowering HbA1c and 
minimising the 
required insulin dose). 

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Treatment algorithm for diabetes mellitus type 2 treatment (con’t)
Combination of basal 
insulin with GLP-1 
receptor agonists may 
be helpful in some 
patients. 
1 Metformin is contraindicated in patients at risk of lactic acidosis such as those with significant renal dysfunction (e.g., 
serum creatinine values >1.5 mg/dL [males] and >1.4 mg/dL [females]) or alcoholism. Metformin should be used 
with caution for patients with conditions that predispose them to risk of hypoxia (congestive heart failure, chronic 
obstructive pulmonary disease or obstructive sleep apnea), liver dysfunction, and age > 80 years (because of the 
decline in renal function).
2 At any stage insulin therapy can be augmented with human amylin analogs (pramlintide)

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References
P14-04357
Institute for clinical system improvement (ICSI). Health Care Guidelines. 
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults. 2012. 
Website: icsi.org
P13-07800
Powers AC. Chapter 344. Diabetes Mellitus. In: Longo DL, Fauci AS, Kasper 
DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison's Principles of Internal 
Medicine. 18th ed. New York: McGraw-Hill; 2012. Website: 
accessmedicine.com.ezp-prod1.hul.harvard.edu/content.aspx?aID=9141196. 
Accessed November 28, 2012.
P12-05315
Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in 
type 2 diabetes: a patient-centered approach: position statement of the American 
Diabetes Association (ADA) and the European Association for the Study of 
Diabetes (EASD). Diabetes Care 2012;35:1364-79.
P13-07680
Day C. ADA-EASD diabetes guidance: individualised treatment of 
hyperglycaemia. British Journal of Diabetes & Vascular Disease 2012;12:146-
151
P13-07681
Qaseem A, Humphrey LL, Sweet DE, Starkey M, Shekelle P, for the Clinical 
Guidelines Committee of the American College of Physicians. Oral 
Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practice 
Guideline From the American College of Physicians Ann Intern Med. 
2012;156:218-231.
R11-4845
American Association of Clinical Endocrinologists (AACE) Medical 
Guidelines for Developing a Diabetes Mellitus Comprehensive Care Plan. 
2011. Website: aace.com/files/dm-guidelines-ccp.pdf
R12-1745
National Institute for Health and Clinical Excellence (NICE). Type 2 diabetes: 
The management of type 2 diabetes. 2009

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ANNEX 3.4 EXAMPLE STUDY SHELL TABLES
Table A1 
Characteristics of Diabetes Therapy Users
Diabetes Therapy Users
Characteristic
Linagliptin
Sitagliptin
Saxagliptin
Alogliptin
Pioglitazone
2nd Generation 
Sulfonylureas 
Number of patients
Number naïve new users
CHARACTERISTICS OF INITIATION
Initiation as monotherapy
Concomitant initiation of other specific hypoglycemic 
agents – Any agent
Concomitant initiation of linagliptin
Concomitant initiation of sitagliptin
Concomitant initiation of saxagliptin
Concomitant initiation of metformin
Concomitant initiation of sulfonylureas
Concomitant initiation of glitazones
Concomitant initiation of meglitinides
Concomitant initiation of AGI
Concomitant initiation of non-insulin injected agents
(exenatide, liraglutide, albiglutide)
SGLT2 inhibitors (Canagliflozin, dapagliflozin)
Concomitant initiation of insulin – any formulation
Concomitant initiation of short-acting insulin
Concomitant initiation of rapid-acting insulin
Concomitant initiation of intermediate-acting insulin
Concomitant initiation of long-acting insulin
Concomitant initiation of insulin mixtures
Initiation as component of dual therapy
Initiation as component of ≥3 therapies
Initiation as fixed-dose combination of two agents
PRIOR USE OF OTHER 
HYPOGLYCEMIC AGENTS

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Table A1 (cont’d)
Characteristics of Diabetes Therapy Users
Diabetes Therapy Users
Characteristic
Linagliptin
Sitagliptin
Saxagliptin
Alogliptin
Pioglitazone
2nd Generation 
Sulfonylureas 
Previous use of other specific hypoglycemic agents – Any 
agent
Previous use of linagliptin
Previous use of sitagliptin
… (List as above)
Current use of other specific hypoglycemic agents – Any 
agent
Concomitant use of linagliptin
Concomitant use of sitagliptin
… (List as above)
Past use of other specific hypoglycemic agents – Any 
agent
Past use of linagliptin
Past use of sitagliptin
… (List as above)
DEMOGRAPHICS
Age (Mean, SD)
Age category 18-35
Age category 36-49
Age category 50-64
Age category 65-74
Age category 75+
Sex
Baseline year
Comorbidity score, Charlson
HEALTH CARE UTILIZATION
Total N distinct non-insulin hypoglicemic agents 
prescribed in past 180 days
Total N distinct pharmacological agents prescribed in past 
180 days
N physician visits
Hospitalization (Y/N)

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Table A1 (cont’d)
Characteristics of Diabetes Therapy Users
Diabetes Therapy Users
Characteristic
Linagliptin
Sitagliptin
Saxagliptin
Alogliptin
Pioglitazone
2nd Generation 
Sulfonylureas 
N hospitalizations
N hospital days
Hospitalization in 30 days prior to treatment initiation
Total N distinct ICD9 diagnoses at the 3rd digit level
Number of laboratory tests ordered
Number of hemoglobin A1C tests ordered
Number of glucose tests ordered
Number of lipid tests ordered
Number of creatinine tests ordered
Mammography
Pap test
PSA test
Colonoscopy
Fecal occult blood test
Flu shot
Pneumococcal vaccine
BMD testing 
Number of electrocardiograms 
Long-term (current) use of insulin
Use of glucose test strips
LABORATORY TESTS
HbA1c (%)
Creatinine (mg/dl)
eGFR (ml/min per 1.73 m2)
Total cholesterol (mg/dl)
HDL level (mg/dl)
LDL level (mg/dl)
Triglyceride level (mg/dl)
COMORBIDITIES AT BASELINE
Diabetes during pregnancy

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Table A1 (cont’d)
Characteristics of Diabetes Therapy Users
Diabetes Therapy Users
Characteristic
Linagliptin
Sitagliptin
Saxagliptin
Alogliptin
Pioglitazone
2nd Generation 
Sulfonylureas 
PCOS
Female Infertility
Precocious puberty
Hyperglycemia
Diabetic ketoacidosis
Hyperosmolar hyperglycemic nonketotic syndrome 
(HONK)
Diabetes with coma
Hypoglycemic coma
Hypoglycemia
Diabetic retinopathy
Diabetic nephropathy NOS
Opthalmology visit
Diabetes with ophthalmic manifestations
Cataract
Glaucoma
Retinal detachment, vitreous hemorrhage, vitrectomy
Pyelonephritis/infections of kidney
Diabetic neuropathy
Mononeuropathy or polyneuropathy
Peripheral autonomic neuropathy
Gastroparesis
Peripheral vascular disease or PVD surgery
Deep vein thrombosis and venous embolism
Diabetes with peripheral circulatory disorders
Coronary atherosclerosis
Atherosclerosis
Aortic aneurysm and dissection
Other aneurysm of artery of lower extremity
Atherosclerosis of extremity with ulceration
Peripheral vascular disease

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Table A1 (cont’d)
Characteristics of Diabetes Therapy Users
Diabetes Therapy Users
Characteristic
Linagliptin
Sitagliptin
Saxagliptin
Alogliptin
Pioglitazone
2nd Generation 
Sulfonylureas 
Arterial embolism and thrombosis of lower extremity
Peripheral angiopathy
Gangrene 
Diabetic foot
Amputation 
Osteomyelitis
Osteoporosis 
Skin infections
Skin ulcer
Chronic ulcer of skin
Diabetes with other specified manifestations 
Diabetes with unspecified complication
Diabetic bone changes 
Erectile dysfunction
Nutrition counseling
Diabetes education
Podiatry
Urinary tract infection
Renal Dysfunction
Acute Renal Disease
Chronic Renal Insufficiency
Diabetic Nephropathy
Hypertensive Nephropathy
Miscellaneous Renal Insufficiency
Prior chronic liver disease and cirrhosis
Prior other liver disease
Porphiria
Hypertension
Hyperlipidemia
Congestive heart failure

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Table A1 (cont’d)
Characteristics of Diabetes Therapy Users
Diabetes Therapy Users
Characteristic
Linagliptin
Sitagliptin
Saxagliptin
Alogliptin
Pioglitazone
2nd Generation 
Sulfonylureas 
Edema
Acute MI
Old MI
Unstable angina
Stable angina
Other chronic ischemic heart disease
CABG
Transmyocardial revascularization
PTCA or atherectomy
Stent
CABG or PTCA or atherectomy or Stent
History of PTCA
History of CABG
Injection/infusion of thrombolytic agent (Alteplase, 
Anistreplase, Reteplase, Streptokinase, Tenecteplase, 
Tissue plasminogen activator, Urokinase)
Rheumatic/aortic/mitral valve disease
Other cardiovascular disorders
Cardiac dysrhythmia
Atrial fibrillation or flutter
Ventricular fibrillation or flutter 
Other dysrythmias
Cardiac conduction disorders
History of sudden cardiac arrest
Ischemic stroke
Late effects of cerebrovascular disease
TIA
Personal history of stroke
Hemorrhagic stroke
COPD
Asthma

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Table A1 (cont’d)
Characteristics of Diabetes Therapy Users
Diabetes Therapy Users
Characteristic
Linagliptin
Sitagliptin
Saxagliptin
Alogliptin
Pioglitazone
2nd Generation 
Sulfonylureas 
Obstructive sleep apnea
Oxygen 
Pneumonia
Polyuria, Nocturia
Polydipsia
Acidosis
Asthenia/fatigue
Syncope and collapse
Abdominal pain
Nausea and/or vomiting
Diarrhea
Pancreatitis
Hyperthyroidism
Hypothyroidism
Other disorders of thyroid gland
Osteoarthritis
Rheumatoid arthritis
Other arthritis, arthropathies and musculoskeletal pain
Fractures
Falls
Anemia
Folate/vit-12 deficiency or vitamin B12 deficiency 
anemia
Haemostatic disorders
Convulsions or seizures NOS
Depression
Bipolar disorder
Anxiety disorders
Sleep disorder
Dementia
Delirium

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Table A1 (cont’d)
Characteristics of Diabetes Therapy Users
Diabetes Therapy Users
Characteristic
Linagliptin
Sitagliptin
Saxagliptin
Alogliptin
Pioglitazone
2nd Generation 
Sulfonylureas 
Psychosis
LIFE STYLE FACTORS
Alcohol abuse or dependence
Drug abuse or dependence
Smoking 
Obesity
Overweight
Abnormal weight gain
MEDICATIONS
ACE inhibitor
ARB
Beta blocker
Thiazides 
Loop diuretics
Other diuretics
Other antihypertensives
Calcium channel blockers
Nitrates
Aliskiren
Digoxin
Antiarrhythmics
Statins
Other lipid-lowering drugs
Colesevelam 
Bromocriptine 
Pramlintide
Oral anticoagulants
Heparin and other LMWH
Other anticoagulants
Aspirin

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Table A1 (cont’d)
Characteristics of Diabetes Therapy Users
Diabetes Therapy Users
Characteristic
Linagliptin
Sitagliptin
Saxagliptin
Alogliptin
Pioglitazone
2nd Generation 
Sulfonylureas 
Antiplatelet
Oral corticosteroids
Nonselective nonsteroidal anti-inflammatory drugs
Selective COX-2 inhibitors
Bisphosphonates
DMARDs
Opiates
Antidepressants
Antipsychotics
Anticonvulsants
Lithium
Benzodiazepines
Other anxiolytics/hypnotics
Agents for dementia
Antiparkinson agents
This table will be tabulated for the population overall and stratified by new user/naive new 
user/non-naive new user. 
Table A2 
Follow-up and outcomes among matched cohorts
Group
Size 
Follow-up (P-Y)
Outcome events
Incidence 
Rate
HR
95% CI
Linagliptin N
ComparatorN
This table will be repeated for each of the outcomes

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Table A3 
Follow-up and distribution of reasons for discontinuation
Group
Size
Follow-up (years)
Reasons for discontinuation (N, %)
Mean
Median
Max
Discontinue 
Switch
Event
Disenrollment
Death
Linagliptin
N
Comparator
N
This table will be repeated for each of the outcomes.

Boehringer Ingelheim
Page 93 of 96
Protocol for observational studies based on existing data
BI Study Number 1218.163
c02611829-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table A4 
Stratifications
Subgroup
Group
Size 
Follow-up (P-
Y)
Outcome events
Incidence Rate
HR
95% CI
Age 18-35
Linagliptin
N
Comparator
N
Age 36-49
Linagliptin
N
Comparator
N
Age 50-64
Linagliptin
N
Comparator
N
Age 65-74
Linagliptin
N
Comparator
N
Age 75+
Linagliptin
N
Comparator
N
This table will extend to encompass all of the stratification variables and will be repeated for 
each of the outcomes.

Boehringer Ingelheim
Protocol for observational st
BI Study Number 1218.163
Proprietary confidential information © 
ANNEX 3.5  EXAMPLE ST
T2DM Type 1 diabetes mellitu
T1DM: Type 1 diabetes mellit
DPP-4: Dipeptidyl peptidase-4
Figure A1
Patient 
tudies based on existing data
2014 Boehringer Ingelheim International GmbH or one or more of 
UDY FIGURES
us
tus
4 
Selection Flow Diagram (CONSORT Style
Page 94 of 96
c02611829-01
f its affiliated companies
e) 

Boehringer Ingelheim
Page 95 of 96
Protocol for observational studies based on existing data
BI Study Number 1218.163
c02611829-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Separate figures to be created for each of the study outcomes.
Figure A2
Survival curves (time to event)
The actual figures will be displayed in the study report.

Boehringer Ingelheim
Page 96 of 96
Protocol for observational studies based on existing data
BI Study Number 1218.163
c02611829-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Separate figures to be created for each of the stratification variables, and for each of the study 
outcomes.
Figure A3
Survival curves (time to event) within subgroup strata
The actual figures will be displayed in the study report.

 
 
 
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