Prevalence of Cardiovascular Disease in Swedish Patients With Type 2 Diabetes and in Patients Initiating on Empagliflozin
Conditions: Type 2 Diabetes Mellitus
Sponsor: Boehringer Ingelheim

 
 
Study Protocol 
 
Title: 
Prevalence of cardiovascular disease in Swedish patients with type 
2 diabetes and in patients initiating on Empagliflozin (ATC code 
A10BK03)  
Study code 
F_07_2018 
Responsible 
statistician: 
 
Responsible project 
epidemiologist: 
. 
Date of Study 
Protocol: 
22-Feb-2018 
Version: 
0.2 
Page 1 of 10 
 
 
 

 
Table of Contents 
List of abbreviations ................................................................................................................... 3 
Introduction ................................................................................................................................ 4 
Research question and objectives ............................................................................................... 5 
Research questions ................................................................................................................. 5 
Objectives ............................................................................................................................... 5 
Primary objectives .............................................................................................................. 5 
Secondary objectives .......................................................................................................... 5 
Subject sets analyzed .................................................................................................................. 5 
Source population in the study ............................................................................................... 5 
Index date ............................................................................................................................... 6 
Baseline and look back period................................................................................................ 6 
Established CVD .................................................................................................................... 6 
Initiation on Empagliflozin..................................................................................................... 7 
Other variables........................................................................................................................ 7 
Demographics and clinical baseline variables.................................................................... 7 
Planned analysis ......................................................................................................................... 9 
Summary of study populations identification......................................................................... 9 
Main analysis .............................................................................................................................. 9 
Data management ....................................................................................................................... 9 
Statistical software.................................................................................................................... 10 
Quality control .......................................................................................................................... 10 
References ................................................................................................................................ 10 
 
 
 
 

List of abbreviations 
 
Term 
Definition / description 
BMI 
Body mass index 
CDR 
Cause-of-Death register 
CI 
Confidence interval 
eGFR 
Estimated glomerular filtration rate 
HbA1c 
Glycated haemoglobin A1c 
HDL 
High Density Lipoprotein 
 
 
 
 
ICD-10 
International classification of diseases 
 
 
 
 
MI 
Myocardial infarction 
 
 
NDR 
National diabetes register 
 
 
NPR 
National patient register 
PH 
Proportional hazards 
PS 
Propensity score 
 
 
RR 
Relative risk 
 
 
 
 
 
 
SPDR 
Swedish prescribed drug register 
T1DM 
Type 1 diabetes mellitus 
T2DM 
Type 2 diabetes mellitus 
 
 
 
 

Introduction 
The Swedish National Diabetes Register (NDR) was launched in 1996 for the purpose of 
promoting evidence-based development of diabetes care. The NDR has been online since 
April 2002 (www.ndr.nu), allowing individual clinics to quickly monitor their activities on a 
regular basis. The register offers a unique opportunity to monitor the quality of care in terms 
of risk factors and the potential complications of diabetes. The results generated by the 
register have been presented at many international meetings and conferences. To our 
knowledge, the NDR is the largest diabetes register in the world. 
Patients with Type 2 diabetes mellitus (T2DM) are at high risk for developing cardiovascular 
disease (CVD) complications. 
The EMPA-REG OUTCOME (ERO) trial demonstrated a reduction in cardiovascular death, 
hospitalization from heart failure and all-cause mortality. Empagliflozin also reduces the risk 
for new onset or worsening of nephropathy, progression to macroalbuminuria and doubling of 
serum creatinine accompanied by eGFR of ≤45 ml/min/1,73 m2. Empagliflozin is also 
associated with weight loss. (1)  
In the ERO patients had a history of CV disease. (Appendix 1). It is not known how many of 
patients in clinical practice have a history of CV disease according to the ERO definition. In a 
publication by Norhammar et al patients with CVD was approximately 34 %. (2)However 
those data also included patients with atrial fibrillation and excluded patients with peripheral 
artery disease. 
According to newly published Swedish guidelines by both the National board of Health and 
Welfare and the Medical Products Agency patients with type 2 diabetes and cardiovascular 
disease start treatment with Empagliflozin. (3) It is not known how many patients with T2DM 
and cardiovascular disease receive empagliflozin today.  
 
 

Research question and objectives 
 
Research questions 
1. Describe the prevalence of T2DM patients with established CVD according to ERO 
study definition in a Swedish population. (Appendix 1). 
2. Describe the prevalence of established CVD according to ERO study definition in 
patients with T2DM who initiates treatment with empagliflozin. 
 
 
Objectives 
 
Primary objectives 
1. To estimate the point prevalence of cardiovascular disease among persons with T2DM 
at 2017-12-31. 
2. To estimate the prevalence of cardiovascular disease among persons with T2DM who 
initiates treatment with empagliflozin between 2015-01-01 and 2017-12-31 
 
Secondary objectives 
1. Describe the T2DM patients with established CVD according to ERO study definition 
with respect to demographics and disease characteristics. 
2. Describe the patients initiating with empagliflozin with respect to demographics and 
disease characteristics. 
 
Subject sets analyzed 
Source population in the study 
 
The broad study population will include patients with T2DM and at least one registration in 
the NDR (at any time from start of registry until 2017) and who are alive on 2015-01-01. 
Based on this population, the following two sub-populations will be identified, corresponding 
to each of the two research questions: 
 
Table 1 Populations 
Population 
Definition 
Details 
Data 
source 
Broad 
population 
Patients with T2DM and at least one 
registration in the NDR (at any time from start 
of registry until 2017) and alive on 2015-01-01 
 
NDR 
Population 1 
Among the broader study population, those 
who are alive also on 2017-12-31 will be 
included. 
 
NDR 
Population 2 
Among the broader study population, those 
SPDR used to NDR 

 
 
 
Index date 
 
The index date for question 1 will be 2017-12-31. For question 2, the index date will be the 
date corresponding to the first collection of empagliflozin. 
 
Baseline and look back period 
To characterize the study population, all information available during the look-back (pre-
index) time period will be collected.  
The look-back time period is defined as the time period ending on the day before the index 
date (Table 2). 
 
Table 2 Data sources with look-back periods and total data collection periods 
 
Established CVD 
 
who initiate on empagliflozin (ATC code 
A10BK03) between 2015-01-01 and 2017-12-
31 will be included 
determine 
population 
Data source 
Data holder 
Look-back 
period 
Total data 
collection period 
National diabetes register 
(NDR) 
Centre of Registers, 
Region Västra Götaland 
1 year 
1996-2017 
Swedish prescribed drug 
register (SPDR) 
National Board of Health 
and Welfare 
 
2015.01.01-
2017.12.31 
National patient register (NPR), 
both inpatient3 and outpatient4 
registers 
National Board of Health 
and Welfare 
1997-index 
date (i.e. as 
long as data 
allows) 
1997-2017 
Cause of death register (CDR) 
National board of health 
and welfare 
Will be used 
to establish the 
broader 
population and 
population 2 
(i.e to 
establish that 
patients are 
alive) 
2017 

Table 3 Established CVD 
 
Initiation on Empagliflozin 
 
Table 4 Initiation of empagliflozin 
 
Other variables 
 
Demographics and clinical baseline variables 
 
Table 5 Demographics and other baseline variables 
Variable 
Definition 
Details 
Data 
source 
Established 
CVD 
Presence of at least one of the ICD10 codes as 
defined in appendix 1 
NPR 
introduced 
ICD10-codes 
in 1997, i.e. 
data from that 
year and later 
will be used 
NPR 
inpatient 
and 
outpatient 
Variable 
Definition 
Details 
Data 
source 
Date for 
initiation of 
empagliflozin 
The date for first collection of Empagliflozin 
(ATC code  A10BK03) 
Index date for 
Question 2 
SPDR 
Variable 
Definition 
Details 
Data source 
Age at index 
Patient age at index. 
Evaluated at the index date. 
Continuous 
NDR 
 
Sex 
Patient sex. 
Evaluated at index date.  
Categorical: 
Female 
Male 
NDR 
 
BMI  
Patient BMI value at index date. 
Evaluated at index date. 
Continuous 
 
 
NDR 
 
Smoking status  Patient smoking status at index date.  
Evaluated at the index date. 
Categorical: 
Yes 
NDR 
 

No 
HbA1c value 
(in mmol/mol) 
Patient HbA1c measurement value at index 
date in mmol/mol. 
Evaluated at the index date. 
Continuous 
 
 
NDR 
 
Duration of 
diabetes at index 
date 
Time difference between [index date] and 
[first type 2 diabetes diagnosis date]. 
Evaluated at the index date. 
 
Continuous 
 
NDR 
 
Systolic blood 
pressure 
Patient systolic blood pressure measurement 
value in mm Hg at then index date. 
Evaluated at the index date. 
Continuous 
  
NDR 
Diastolic blood 
pressure 
Patient diastolic blood pressure measurement 
value in mm Hg. 
Evaluated at the index date. 
Continuous 
 
NDR 
Total cholesterol Patient Total cholesterol measurement 
Evaluated at the index date. 
Continuous 
NDR 
LDL 
Patient LDL measurement value in mmol/L. 
Evaluated at the index date. 
Continuous 
 
NDR 
HDL 
Patient HDL measurement value in mmol/L. 
Evaluated at the index date. 
Continuous 
 
NDR 
Triglyceride 
Patient Triglyceride measurement value at 
index date in mmol/L. 
Evaluated at the index date. 
Continuous 
 
 
NDR 
 
Creatinine 
Patient Creatinine measurement 
Evaluated at the index date. 
Continuos 
NDR 
Estimated 
glomerular 
filtration rate 
(eGFR) 
Patient eGFR at index date estimate derived 
from serum creatinine measurement using the  
CKD-Epi equation: 
eGFR (mL/min/1.73 m2) = 141 x 
min(Scr/K,1)a x max(Scr/K,1)-1.209 x 0.993Age x 
1.018 [if female]. 
a = -0.329 (females) or -0.411 (males).  
Evaluated at the index date. 
Continuous 
 
NDR 
Micro 
albuminurea 
Evaluated at the index date. 
Categorical: 
Yes 
NDR 
 

 
 
Planned analysis 
Summary of study populations identification 
The identification process used to identify the study populations and subgroups will be 
summarized using population flowcharts including the following information: 
• The total number of patients in the broad population (i.e. patients with T2DM and with 
at least one registration in the NDR and who are alive on 2015-01-01). 
• The number of patients who are also alive on 2017-12-31 (the population for Question 
1). 
• The number of patients collecting Empagliflozin between 2015-01-01 and 2017-12-31 
but who are not part of the broad population 
• The number of patients in the broad population initiating Empagliflozin between 
2015-01-01 and 2017-12-31 (the population for question 2) 
Main analysis 
 
All analyses will be descriptive and no testing of hypotheses will be performed. The number 
and percentage of subjects with established CVD will be calculated and reported for both 
questions. 
 
Variables in Table 5 will be descriptively reported for patients with established CVD within 
population 1 as well as for all patients in population 2. 
 
Relating to question 2, the sub-group of patients initiating Empagliflozin during 2017 will be 
described with respect to prevalence of established CVD as well as the demographic and 
disease characteristics of Table 5. 
Data management 
 
No 
Macro 
albuminurea 
Evaluated at the index date. 
Categorical: 
Yes 
No 
NDR 
 
Retinopathy 
Evaluated at the index date. 
 
NDR 
Lipid lowering 
drugs 
Evaluated at the index date. 
 
NDR 
Blood pressure 
lowering drugs 
Evaluated at the index date. 
 
NDR 
Diabetes drugs 
Evaluated at the index date. 
 
NDR 

Statistical software 
The analysis and data management will be performed using SAS 9.4® or R 3.4.0.  
R language is described in more details in report "R: Regulatory Compliance and Validation 
Issues: A Guidance Document for the Use of R in Regulated Clinical Trial Environments" 
(www.r-project.org/doc/R-FDA.pdf, read 21 December 2016). 
 
Quality control 
Programs used in the data management and statistical analysis will be validated though 
independent review of the programming code, analysis data and output based on a risk 
assessment. 
References 
 
1. Zinman et al. Empagliflozin, cardiovascular outcomes, and mortality in Type 2 
diabetes. N Engl J Med 2015; 373:2117-2128 
 
2. Norhammar et al. Incidence, prevalence and mortality of type 2 diabetes requiring 
glucose-lowering treatment, and associated risks of cardiovascular complications: a 
nationwide study in Sweden, 2006–2013. Diabetologia (2016) 59:1692–1701 
 
3. Socialstyrelsen. 2017. Nationella riktlinjer för diabetesvård. Retrieved from 
http://www.socialstyrelsen.se/Lists/Artikelkatalog/Attachments/20633/2017-5-31.pdf