Caracterización de Subgrupos de Diabetes Tipo 2 al diagnóstico: un Paso Necesario Hacia la Medicina de precisión en Diabetes.
Conditions: Characteristics Disease, Type 2 Diabetes
Sponsor: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau

 
 
 
 
 
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STUDY PROTOCOL 
 
Characterization of type 2 diabetes subgroups at diagnosis: a necessary step towards 
precision medicine in diabetes. 
 
Protocol version and date 
Version: 1.0 Date: 07/17/2021 
Protocol Code 
IIBSP-CDM- 2021-01 
Sponsor 
 
Fundació Institut de Recerca de l'Hospital de la 
Santa Creu i Sant Pau 
saint Quinti , 89 
08041 Barcelona 
Phone: 93 5565661 
Fax: 93 5565602 
Coordinator Researcher 
Dídac Mauricio, Department of Endocrinology and 
Nutrition 
Hospital of Santa Creu i Sant Pau 
saint Quinti , 89 
08041 Barcelona 
Tel: 627953473 
e-mail: dmauricio@santpau.cat 
Principal researchers 
Dídac Mauricio, Endocrinology and Nutrition 
Service 
Hospital of Santa Creu i Sant Pau 
saint Quinti , 89 
08041 Barcelona 
Phone: 627953473 
e-mail: dmauricio@santpau.cat  
 
Number of protocol pages 
80 
This Study Protocol is the property of the Fundació Institut de Recerca de 
l'Hospital de la Santa Creu i Sant Pau, and is a confidential document. It must not 
be copied or distributed to other parties without the prior written permission of the 
Research Institute. 
 
 
 
 

 
 
 
 
 
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Contents 
1.  SUMMARY:  ......................................................................................................... 5 
2.  ABSTRACT  .......................................................................................................... 8 
3.  THEORETICAL FRAMEWORK, PROBLEM STATEMENT:  .......................... 9 
3.1 Background  .......................................................................................................... 9 
3.1.1 Heterogeneity of type 2 diabetes mellitus  .................................................... 9 
3.1.2 Current aspects of precision medicine in diabetes ...................................... 10 
3.2 Rationale  ............................................................................................................ 13 
4.  HYPOTHESIS, PRIMARY AND SECONDARY OBJECTIVES  ..................... 14 
4.1 Assumptions  ...................................................................................................... 14 
4.2 Primary Target:  .................................................................................................. 14 
4.3 Secondary Objectives:  ....................................................................................... 15 
5.  METHODS:  ......................................................................................................... 16 
5.1 Study design  ...................................................................................................... 16 
5.2 Study period  ....................................................................................................... 16 
5.2.1 Recruitment period  ..................................................................................... 16 
5.3 Follow-up of participants and linkage with other databases  ............................. 16 
5.4 Study population  ................................................................................................ 17 
5.5 Selection criteria  ................................................................................................ 17 
5.5.1 Inclusion criteria:  ........................................................................................ 17 
5.5.2 Exclusion criteria:  ....................................................................................... 18 
5.5.3 Withdrawal criteria:  .................................................................................... 18 
5.6.1 Preselection  ................................................................................................. 18 
5.6.2 Inclusion  ..................................................................................................... 19 
5.6.3 Samples  ....................................................................................................... 20 
5.7 Variables  ............................................................................................................ 21 
5.7.1 Main variables  ............................................................................................ 21 
5.7.2 Other relevant variables  .............................................................................. 22 
5.8 Specific sub-studies  ........................................................................................... 22 
5.8.1 Sub-study on diet and physical activity  ...................................................... 23 
5.8.2 Sub-study on advanced lipoprotein profiling  ............................................. 23 
5.8.3 Sub-study on subclinical carotid and femoral atherosclerosis .................... 24 
5.8.4 Sub-study on initial antidiabetic treatment and other diabetes-related 
therapies  ............................................................................................................... 24 
5.8.5  
Metabolomic and genetic sub-studies related to diabetes  ..................... 25 
6. DATA COLLECTION AND ANALYSIS .............................................................. 32 

 
 
 
 
 
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6.1 Data collection schedule  .................................................................................... 32 
7. DATA HANDLING  ................................................................................................ 37 
7.1 Data collection and confidentiality  .................................................................... 37 
7.2 Mandatory requirements of the Data Protection Law regulation (EU) No. 
2016/679 and Organic Law 3/2018 Protection of Personal Data and digital rights 
guarantee (RGPD)  ................................................................................................... 38 
7.2.1 Identification of the data and the subjects that process them  ..................... 38 
7.2.2 Identification of the treatments and legitimizing basis of the treatments  ... 38 
7.2.3 Tools used to process the data  .................................................................... 39 
7.2.4 Procedure for linking data with SIDIAP/PADRIS  ..................................... 40 
7.2.5 International data transfers  ......................................................................... 40 
7.2.6 Identification of treatments that may pose a high risk to the rights and 
freedoms of the participants in the research project.  ........................................... 41 
7.2.7 Rights of interested persons  ........................................................................ 41 
7.2.8 Data validation and quality control  ............................................................ 42 
8. WORK PLAN (tasks, milestones and study timeline):  ........................................... 44 
9. ETHICAL ASPECTS:  ............................................................................................. 46 
9.1 Benefit-risk evaluation of the research  .............................................................. 47 
9.2 Ethical considerations, regarding information to subjects and informed consent 
 .................................................................................................................................. 47 
9.3 Considerations for the treatment of biological samples  .................................... 48 
9.3 Confidentiality of data  ....................................................................................... 49 
9.4 Interference with the physician's prescribing habits  .......................................... 49 
10. PLANS FOR DISSEMINATION OF RESULTS:  ................................................ 49 
11. RESOURCES FOR CONDUCTING THE STUDY  ............................................. 49 
12. AMENDMENTS TO THE PROTOCOL:  ............................................................. 51 
ANNEX 1. DATA COLLECTION NOTEBOOK  ...................................................... 60 
ANNEX 2. COMMITMENT OF THE PRINCIPAL INVESTIGATOR AND 
COORDINATOR  ........................................................................................................ 61 
ANNEX 3. RESEARCHER COMMITMENT  ........................................................... 62 
ANNEX 4.  
CONFORMITY OF THE CEI  ........................................................... 62 
ANNEX 5. PATIENT INFORMATION SHEET  ....................................................... 63 
ANNEX 6. INFORMED CONSENT FORM  ............................................................. 71 
ANNEX 7. FINANCIAL REPORT  ............................................................................ 76 
ANNEX 8. Center characteristics and expected results  .............................................. 77 
ANNEX 9. Impact assessment related to data protection for health research and 
innovation projects (attached separately)  ............ Error! No s'ha definit el marcador. 

 
 
 
 
 
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ANNEX 10. Questionnaires related to physical activity and dietary habits  .. Error! No 
s'ha definit el marcador. 
ANNEX 11. Study promotional material to recruit patients  ....................................... 78 
ANNEX 12. List of centers, principal investigators centers  ....................................... 79 
ANNEX 13. Budget  ............................................. Error! No s'ha definit el marcador. 
 

 
 
 
 
 
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GLOSSARY OF TERMS 
 
T2DM: type 2 diabetes mellitus 
CAP: primary care centers 
HT: antihypertensive treatment 
GAD: glutamic acid decarboxylase antibodies / anti -glutamic acid decarboxylase 
antibodies 
BMI: body mass index 
HbA1c: glycosylated hemoglobin 
HOMA-B: homoeostasis model estimate of β- cell function / β -cell function 
homeostasis model estimates 
HOMA-IR: homoeostasis model estimate of insulin resistance / insulin resistance 
SAID: severe autoimmune diabetes 
SIDD: severe insulin-deficient diabetes 
SIRD: severe insulin-resistant diabetes 
MOD: mild obesity-related diabetes  
MARD: mild age-related diabetes  
 
 
 
 
 
 
 
 

 
 
 
 
 
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1. SUMMARY: 
Promoter identification 
Santa Creu and Sant Pau Hospital Research Institute - 
IIB Sant Pau 
c / Sant Antoni Maria Claret , 167 
08025 Barcelona 
Tel: 93 553 78 69 
Study Title 
Characterization of subgroups of type 2 diabetes mellitus 
at diagnosis: a necessary step towards precision 
medicine in diabetes, COPERNICAN study 
Protocol code 
IIBSP-CDM- 2021-01 
Protocol version and date 
Version: 1.0 Date: 07/17/2021 
Coordinating researcher 
Dídac Mauricio, Department of Endocrinology and 
Nutrition 
Hospital of Santa Creu i Sant Pau 
saint Quinti , 89 
08041 Barcelona 
Tel: 627953473 
e-mail: dmauricio@santpau.cat 
Principal investigator 
 
Dídac Mauricio, Department of Endocrinology and 
Nutrition 
Hospital de la Santa Creu y Sant Pau 
c / Sant Antoni Maria Claret , 167 
08025 Barcelona 
Tel: 627953473 
e-mail: DMauricio@santpau.cat 
 
Collaborating researchers 
 
Lleida CAPs : 
 
 
• Neus Miró 
• Jesus Pujol 
• Monica Solanes 
• Antonieta Lafarga 
• Sandra Guerrero 
• Mireia Marin 
 
Barcelona CAPs : 
 
• Begoña Ribas 
• Natalia Riera 
• Ana M. Pedro Pijoan 
• Manel Mata 
• Helena Hernández Boluda 
• Xavier Cos 
 

 
 
 
 
 
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USR Lleida  
• Marta Ortega 
• Eva Artigues 
• Inés García 
• Laura Azlor 
• Joaquim Sol 
 
Karen Rodriguez 
Ferran Primary Care Center (Lleida) 
Minerva Granado 
CIBER for Diabetes and Metabolic Diseases 
(CIBERDEM) 
Cintia González Blanco 
Hospital de la Santa Creu y Sant Pau 
 
Cristina Farras 
Martha Hernandez  
Merce Ibarz 
Maria Bernal Murillo 
Vilanova University Hospital 
 
USR of Barcelona 
Josep Franco 
University of Barcelona 
e-mail: josep.franch@gmail.com 
Jordi Real Gatius 
CIBER of Diabetes and Metabolic Diseases 
(CIBERDEM) 
Emerald Castelblanco 
CIBER of Diabetes and Metabolic Diseases 
(CIBERDEM) 
Bogdan Vlacho (project manager) 
Epidemiological Research Group on Diabetes from Care 
Primary (DAP-CAT) 
Participating centers 
Hospital de la Santa Creu i Sant Pau (IR-HSCSP, 
Barcelona) 
Primary care centers in Lleida and Barcelona 
Lleida Research Support Unit, 
Barcelona Research Support Unit 
CEIC of reference 
CEIm St. Paul 
For ICS centers: 
CEIm IDIAP Jordi Gol i Gurina 
for CAP's Consortium Comprehensive Sanitary: 
Consortium CEIC Comprehensive Sanitary 
Main goal 
This project aims to characterize a large group of people 
with type 2 diabetes mellitus (T2DM) recently diagnosed 
in the Spanish population. 

 
 
 
 
 
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Design 
Observational prospective cohort study 
Disease under study 
Diabetes mellitus type 2 
Methodology 
We will conduct a multicenter prospective observational 
study. The scope of the study is made up of Primary Care 
Centers (CAP) in 2 care areas (Barcelona and Lleida). 
Study procedures will be performed by the local 
investigator, who will not be the subject's usual primary 
care physician. 
Study population and total 
number of subjects 
People with T2DM 
Calendar. 
Expected 
duration of the study. 
From January 2022 to December 2024 (3 years). 
Ethical considerations 
All newly diagnosed subjects with a clinical diagnosis 
of T2DM will be invited to participate and only those 
subjects who sign the informed consent for the study 
will enter the study. 
Funding source 
Instituto de Salud Carlos III Proyecto FIS PI21/01163 
Keywords 
Prospective cohort studies, characterization, T2DM 
 
 
 
 
 
 

 
 
 
 
 
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2. ABSTRACT  
Objectives: Our primary objective is to identify and characterize the relevant 
subgroups (clusters) in type 2 diabetes (T2DM) at the time of diagnosis in our 
region. This objective will be addressed using the 6 main variables (see 
Methodology) that have been used so far in previous studies in other populations 
to develop the clustering of diabetes. Therefore, this is a study in the field of 
diagnostic precision medicine in diabetes. In addition, as secondary objectives we 
will evaluate other phenotypic characteristics of these subgroups (clinical, 
metabolic, and associated comorbidities). 
Methodology: this project will establish a prospective observational cohort study 
of 1200 subjects newly diagnosed with T2DM in 11 primary care centers (PAC) of 
the healthcare areas of Barcelona city (5 CAP) and the territory of Lleida (6 PCC). 
We will identify and evaluate all newly diagnosed cases of T2DM. Participants 
will undergo a comprehensive phenotypic evaluation, including the 6 variables that 
will allow the characterization of T2DM subgroups: age, antibodies against 
glutamic acid decarboxylase (GAD), body mass index, glycated hemoglobin, and 
sensitivity indices (HOMA-IR) and insulin secretion (HOMA beta), based on the 
determination of C-peptide. We will carry out the latest generation cluster analysis 
(k- means and hierarchical clustering), following the method described in previous 
studies using the 6 variables mentioned above. Onset diabetes subgroups and their 
association with secondary outcome variables will be assessed. Other procedures 
of this project include: clinical (including complications) and biochemical 
evaluation, advanced lipoprotein profile, and validated questionnaires for the 
evaluation of diet and physical activity. We will also evaluate the initial 
prescription of antidiabetic medication. 
Keywords: characterization, conglomerates, primary care centers, type 2 diabetes 
 
 
 

 
 
 
 
 
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3. THEORETICAL FRAMEWORK, PROBLEM STATEMENT: 
3.1 Background  
Diabetes mellitus is one of the most prevalent chronic diseases, ranking eighth in 
terms of the global burden of disease measure developed by the world health 
organization-WHO [1]. Specifically, type 2 diabetes (T2DM) is reaching epidemic 
proportions. This is also the case in Spain, where the T2DM prevalence in people 
over 18 years of age is around 14% [2]. Furthermore, diabetes reduces quality of 
life and increases years of life lost, especially due to chronic complications [3]. 
3.1.1 Heterogeneity of type 2 diabetes mellitus 
Traditionally, diabetes is classified into different types: type 1, type 2, gestational 
diabetes, and other specific types of diabetes. However, one of the main problems 
is that T2DM is a diagnosis based on the exclusion of other types of diabetes. This 
has led to the inclusion in the diagnostic category of T2DM, subgroups of subjects 
clearly differentiated from each other in terms of their clinical characteristics, 
especially in terms of response to treatment and development of complications. 
Evidence suggests that T2DM is a highly heterogeneous complex metabolic 
disease encompassing different pathophysiological and genetic characteristics [4, 
5]. Furthermore, the presentation and progression of the disease may vary between 
subjects, leading to poor metabolic and glycemic control [5]. Therefore, it is well 
known that heterogeneity is one of the main problems affecting T2DM. Actually, 
this is an important aspect in terms of disease management and prognosis 
decisions. For example, the response to different treatments varies widely among 
subjects with T2DM [6]; this is clearly leading to a significant proportion (44%) of 
people not achieving good glycemic control [7]. Furthermore, in Europe alone, 
during the period between 2005 and 2017, the European Medicines Agency 
(EMA) has approved 40 new drugs to treat diabetes, mainly for T2DM [8]. Thus, 
we have more complex combinations of treatments without having achieved a 
similar advance in the development of more precise tools to characterize the 
disease itself. Thus, although novel treatments are available, their use and the 

 
 
 
 
 
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individualization of treatment continue to be based on “classic” bases, from which 
considerable variability arises in clinical practice. 
Our group has been a pioneer in research on the characterization of the 
heterogeneity of T2DM in Spain. In fact, we have carried out different studies on 
the so-called subtype of latent autoimmune diabetes in adults (LADA). So far we 
have been able to contribute to the characterization of LADA in Spain by carrying 
out immunological, metabolic, genetic and clinical characterization studies of this 
subtype of diabetes. The result of our research in this field consists of multiple 
articles based on our own cohort [9-12] or with internationally aggregated data 
[13-16]. Although this subtype of diabetes has not yet been accepted by the ADA 
[17], it should be underlined that in 2019 the WHO already included LADA as a 
different type of diabetes under the subset of hybrid forms of diabetes in its 
updated classification [18]. This is a paradigmatic example of what happens in 
terms of diagnosis, prognosis, therapeutic decisions, and follow-up in a different 
subgroup of subjects initially categorized as T2DM. 
3.1.2 Current aspects of precision medicine in diabetes 
Traditional methods using the clinical phenotype and basic physiology have been 
used by clinicians for decades. However, in view of the aforementioned 
complexity of new therapeutic approaches, it is clear that we need to introduce 
new tools in clinical decision making. This should lead to research in deep 
phenotyping and the introduction of advanced molecular tools, including different 
omics [5,20]. This implies a new stratified approach with the use of molecular and 
deep phenotyping, which is, adapting diagnosis or therapeutics (from prevention to 
treatment) to subgroups of populations that share similar characteristics, thus 
minimizing error and risk and maximizing the efficacy (i.e. precision medicine). 
Interestingly, a recent collaboration between the ADA and the EASD issued a 
consensus on the development of precision medicine in diabetes [21]. The full 
landscape of precision medicine includes precision diagnostics, precision 
prevention, precision treatment, precision prognosis, and precision monitoring. For 
this study we will focus solely on precision diagnoses, although the future 

 
 
 
 
 
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knowledge generated by this project and the follow-up of the subjects of this study 
will undoubtedly contribute to the rest of the fields of precision medicine in 
diabetes in our country. 
An accurate diagnosis is a decision based on probability, which is usually made at 
a specific point in the natural history of the disease and is not an absolute or 
permanent state. Taking this into account, diabetes mellitus can be considered as a 
condition in which precision diagnostics should ideally be implemented. T2DM is 
already a paradigm of the need for this novel approach [22-24], but it has yet to 
come into force in routine clinical practice. 
We can consider T2DM as a condition that was defined based on simple a clinical 
phenotypic trait that, however, contains different groups (clusters) of subjects. 
Recently published studies used cluster analyzes to refine the classification of 
T2DM beyond the simple use of blood glucose levels [25-29]. These studies 
identified subgroups of subjects with diabetes mellitus who have specific patterns 
of development of complications. In 2018, the seminal study by the group led by 
Leif Groop in Sweden [25], identified five new groups of subjects using 6 different 
variables, i.e., glutamic acid decarboxylase (GAD) antibodies, age at diagnosis, 
BMI, HbA1c, homeostasis model, cell function estimates β (HOMA-B) and insulin 
resistance (HOMA-IR). According to the grouping of subjects based on these 
phenotypic variables, 5 subgroups were defined: SAID severe autoimmune 
diabetes; SIDD, severe insulin deficiency diabetes; SIRD, severe insulin resistant 
diabetes; MOD, mild obesity-related diabetes; MARD, mild age-related diabetes. 
This classification based on combined information of these 6 variables proved to 
be a more precise and clinically useful stratification than the diagnosis based on a 
single metabolite such as glucose or HbA1c, together with all the traditional 
clinical factors. Another study from Germany studied this comprehensive 
phenotyping in its local diabetic population [26], in which the distribution of 
clusters differed slightly from that reported in the Swedish population-based 
cohort. They observed a higher prevalence of the SAID subtype of diabetes, and a 
lower prevalence of the SIDD subtype in their population and concluded that these 
specific groups showed different metabolic disturbances and patterns of risk of 

 
 
 
 
 
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developing diabetes-related complications [26]. In another similar study from the 
UK, researchers replicated the initial pooling of the German study, in a cohort of 
6,810 people with prediabetes. Six distinct groups were identified: 1: low risk, 2: 
very low risk, 3: β-cell failure, 4: low-risk obesity, 5: high-risk insulin-resistant 
fatty liver, and 6: visceral fatty kidney disease high risk. Although groups 3, 5, and 
6 were associated with higher blood glucose at baseline than the other groups, only 
groups 3 and 5 were associated with a higher risk of T2DM in longitudinal 
analyses. Furthermore, groups 3, 5, and 6 were associated with an increased risk of 
kidney disease [27]. Other investigators have built their research on the initial 
findings of Ahlqvist et al [28, 29], while others applied omics tools to clustering 
based on 6 phenotypic variables [30]. The most representative line of research in 
this line is that developed by the group of J. Florez [24], in which they have been 
able to combine the phenotypic and genetic approach with a combination of 94 
loci that represent the genetic variant of T2DM to develop partitioned scores that 
identified 5 different subgroups of subjects harboring different traits of insulin 
deficiency (beta cell and proinsulin) and insulin resistance (obesity, lipodystrophy, 
and liver lipids) [30]. Furthermore, they were able to relate these groups to relevant 
clinical outcomes (cardiovascular and metabolic complications). Interestingly, the 
existence of different subgroups is not a static image, but a moving one, where the 
trajectory of the subjects in the follow-up does not always necessarily fit into the 
same group; that is, an individual can move from one group to another [ 23,26, 
28,29]. The fact that the initial groups experience different diabetes component 
pathways emphasizes the importance of monitoring the trajectory of the different 
groups and the individuals included [23]. It should be noted that some of the 
studies that replicate the initial study by Ahlqvist et al. [3] do not include the SAID 
cluster in their approach, since it is not, strictly speaking, a subgroup of subjects 
belonging to T2DM once identified. 
Finally, it should be noted that phenotypic characteristics have been shown to be 
associated with response to different drugs [19,28]. Therefore, it is highly relevant 
to initially implement a deeper phenotyping of each population (precision 
diagnoses) in order to further build therapeutics and precision prognosis. 

 
 
 
 
 
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Therefore, future phenomic and genetic characterization of large cohorts in other 
populations is needed to move towards better prediction of T2DM, complications, 
and precision medicine. 
3.2 Justification  
In this context, we strongly believe that the proper characterization of subjects 
clinically categorized as having type 2 diabetes is an important issue. Advances in 
this field should allow us to implement the different strategies of precision 
medicine in our country. It is of the utmost importance that we establish strategic 
initiatives to delve into our own population so that we can implement all the new 
potential tools of precision medicine for the diagnosis, prognosis, prevention and 
treatment of diabetes. Therefore, we think that the current project is fundamental 
as a pioneering study in our country. Our objective is to evaluate and characterize 
the different subtypes of T2DM in our population based on previous work by other 
groups in this field. 
 
 

 
 
 
 
 
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4. HYPOTHESIS, PRIMARY AND SECONDARY OBJECTIVES 
4.1 Assumptions 
 
The previously described subtypes of subjects included in the diagnostic 
category of T2DM at the onset of the disease have been evaluated and confirmed 
in other populations, mainly Caucasians. However, we are not aware of any 
prospective study that is responsible for characterizing the subgroups of diabetes 
with onset in adulthood, especially T2DM, in a sufficiently potentiated sample in 
our country. Therefore, it has not yet been established whether the different 
conglomerates (“clusters”) of adult-onset diabetes subtypes exist in our population. 
Our main hypothesis is that there is also heterogeneity of T2DM in our population, 
characterized by a relevant grouping of subtypes that are potentially similar to 
those described in other European populations. 
We also hypothesize that the different subgroups identified would also show a 
different profile for other phenotypic characteristics that are represented by other 
clinical variables, such as comorbidities (fatty liver, clinical and subclinical 
atherosclerosis), metabolic/genetic characteristics (advanced metabolomics and 
lipoprotein profile, genetic alterations) and life habits (diet and physical activity). 
 
4.2 Primary objective: 
To assess and characterize the relevant subgroups (clusters) of type 2 diabetes at 
diagnosis in our population. 
This objective will be addressed using the 6 main variables that have been used so 
far in previous studies in other populations to develop disease groupings, that is, 
age, GAD antibodies, body mass index, glycosylated hemoglobin (HbA1c), and 
estimates of the evaluation of the homeostatic model 2 of β-cell function and 
insulin resistance. 
 
 

 
 
 
 
 
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4.3 Secondary objectives: 
The study design will allow us to study other characteristics of the study 
subjects and of the disease itself at the time of diagnosis: 
Relevant phenotypic characteristics not included as variables in the main 
objective: 
• Other clinical characteristics (for example, gender) 
• Frequency of various associated comorbidities, including micro and 
macrovascular complications. As additional comorbidities we also 
include: non-alcoholic fatty liver and liver fibrosis scores; Subclinical 
carotid and femoral atherosclerosis. 
• Advanced lipoprotein profile. 
• Lifestyle variables: eating habits and physical activity. 
• Use in real clinical practice of antidiabetics and other treatments at the 
beginning of the disease. 
• Appearance of different micro- and macro-vascular complications of 
diabetes 
• Metabolomics and genetic profile related to diabetes 
 
 

 
 
 
 
 
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5. METHODS: 
5.1 Study design 
We will conduct a multicenter prospective observational study. The study design 
contemplates a single visit that will coincide with the inclusion of the patient in the 
study. Prior to the inclusion visit, a pre-selection period is planned in which the 
possible candidate will be invited, all the study procedures will be explained and 
clarified, the selection criteria will be checked and the inclusion visit will be 
scheduled. 
 
The scope of the study is made up of Primary Care Centers (CAP) in 2 large health 
areas (Barcelona and Lleida). In the Annex 8 section, the characteristics and 
expected recruitment capacity of each CAP are detailed. We have taken a 
conservative approach using the lower range of incidence calculated based on our 
own data from 2019 to 2020. The table provided used an expected acceptance rate 
for participation of 80%. Additionally, CAPs were selected based on commitment 
and performance in our previous studies. It is planned to include 1200 participants 
newly diagnosed with T2DM. Depending on compliance with the recruitment rate, 
the inclusion of other CAPs is possible to achieve the expected number of 
participants in the study. 
 
5.2 Study period 
The study period is three years, from January 1, 2022 to December 31, 2024. 
5.2.1 Recruitment period  
The recruitment period for participants is 2 years, from January 1, 2022 to 
December 31, 2023 
5.3 Follow-up of participants and linkage with other databases 
For this study, a pragmatic follow-up of the participants will be chosen, which is 
adapted to the usual clinical practice for the follow-up of diabetes. For this reason, 
the monitoring will be done from: 

 
 
 
 
 
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• SIDIAP/PADRIS databases, with the link to the electronic medical record 
of the participants who have accepted this option in the informed consent. 
• Electronic medical record, in the event that the link with the 
SIDIAP/PADRIS databases is not possible for technical reasons (non-ICS 
centers), the collection of monitoring variables will be done directly from 
the clinical course (review of clinical history) of participants without 
scheduling additional study follow-up visits. 
• For specific causes of mortality, data linkage with the National Institute of 
Statistics (INE) will be used. 
• If the participants have already participated or are participating in other 
clinical research studies and want to transfer the data they have provided 
for other projects to this study, this linking (portability) of the data will be 
allowed. 
 
All participants will be followed until the end of the study, death or 
withdrawal of informed consent. 
 
5.4 Study population  
People with type 2 diabetes mellitus treated in primary care centers in Barcelona 
and Lleida. 
 
5.5 Selection criteria 
 
5.5.1 Inclusion criteria: 
• Subjects of both sexes, of legal age (≥18 years) 
• Newly diagnosed T2DM according to the criteria of the American Diabetes 
Association  
• With a maximum duration of three months of the disease at the time of 
inclusion. 
• Informed consent signature 
 
 
 
 

 
 
 
 
 
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5.5.2 Exclusion criteria: 
Subjects with a new diagnosis of other types of diabetes (type 1, MODY, 
gestational or other causes) will also be evaluated to ensure that the diagnostic 
criteria for selection are correctly implemented in all potential study participants. 
*For final analysis, subjects with any diagnosis of diabetes other than T2DM will 
be excluded from the study. 
 
5.5.3 Withdrawal criteria: 
All included patients have the right to withdraw from the study at any time, 
withdrawing their consent, without having to justify this decision, and without this 
being detrimental to their clinical follow-up. Likewise, the participant may revoke 
the use of their data in the analysis, without justifying their decision, and without 
this resulting in any liability or damage. 
 
5.6 Study procedures 
This study will be launched in the participating primary care centers, once a 
favorable opinion has been obtained by the CEI, and following the legislative 
requirements for this type of observational study. 
 
5.6.1 Preselection  
Each study subject will be identified by their primary healthcare professional and 
they will notify the main investigator or collaborators of the center through the 
electronic medical record system about the possible candidate. All newly 
diagnosed subjects with a clinical diagnosis of T2DM will be invited to participate. 
The study procedures will be carried out by local researchers in each participating 
center, who in some cases will be the same doctors and nurses as the participants. 
A specific visit will be scheduled with the local investigator at each CAP to 
perform all study procedures in a single visit. 
 
 
 
 
 
 

 
 
 
 
 
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5.6.2 Inclusion 
Each patient invited to participate will be informed about the study both verbally 
and in writing form, providing a document called "Patient Information Sheet" 
(Annex 5). No participant will be included until they have been duly informed by 
the researcher and have freely given their informed consent to participate in the 
study (Annex 6). Once compliance with all the selection criteria has been 
confirmed and informed consent has been granted, data collection will begin by 
completing an electronic case report form (eCRF), intended to record the 
information available in the patient's clinical history, patient or obtained during the 
inclusion visit (Annex 1). 
The inclusion visit will take place within the first 3-month period after the 
diagnosis of T2DM. This will avoid interfering with the regular clinical practice of 
the GP, and will also ensure that we do not interfere with the doctor's prescribing 
habits. Since current clinical practice includes assessment of chronic diabetes 
complications (foot exam, eye disease screening program, microalbuminuria), 
these data will be extracted by linking with electronic record databases 
(SIDIAP/PADRIS) or through the electronic medical record in the event that the 
link with the SIDIAP/PADRIS database is not possible. The pathological 
antecedents of interest (comorbidities), clinical and analytical variables related to 
diabetes before inclusion, will be collected from the clinical history and from the 
SIDIAP/PADRIS databases. All participants will be followed until the end of the 
study, transfer from the SIDIAP/PADRIS databases, specific cause of mortality 
(INE) or withdrawal of informed consent. In each CAP, all the family doctors of 
the CAP will be informed so that they transfer the management of the routine 
initial evaluation of their newly diagnosed cases of T2DM to the investigator of 
the local center; this will prevent further unnecessary routine clinical procedures 
from being performed at the study visit. This measure will surely improve the 
participation of all local general practitioners in the study. Figure 1 describes the 
procedures and data flow in the study. 
 
Initial clinical evaluation of all enrolled subjects will be performed during the 
study enrollment visit. Questionnaires related to lifestyle will be self-administered 

 
 
 
 
 
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during the visit. An appointment will be made for routine blood and urine tests as 
recommended by current guidelines. The laboratory procedures will be carried out 
in the central laboratories of each of the areas (each care area, that is, Lleida and 
Barcelona, has a local central laboratory). All routine clinical biochemical 
parameters will be determined according to standard clinical laboratory 
procedures. Additional laboratory procedures for the determination of C-peptide 
and antibodies that are considered non-routine parameters will also be carried out 
in local laboratories, and the cost is included in the project budget, with the same 
urine and blood sample as the initial analysis. This logistical organization provides 
a unique framework in which all data is included in the usual flow of routine 
clinical information. Thus, the usual clinical team and the participants will have 
access to all the data generated during the study. In addition, after the study visit, 
the local investigator will ensure that the participant gets an appointment for 
routine evaluation of foot and eye complications at the CAP. The data of these 
routine procedures are readily available and will be obtained from the electronic 
medical record. 
 
5.6.3 Samples 
Blood and urine samples will be obtained from all fasting study participants. Each 
biobank belongs to the same institution as the local laboratories, and the transfer of 
biological samples from the local laboratories to the biobanks will be done 
automatically. The samples will be sent and stored (finally deposited) to the central 
Biobank of the promoter at the end of the study. The visual diagram of the circuit 
for sending samples to the biobank is presented in Figure 1. 
 

 
 
 
 
 
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Figure 1. Diagram of study procedures 
 
5.7 Variables 
 
This study aims to include as many baseline phenotypic features as realistically 
possible. Next, we describe the variables that are considered essential, along with 
other additional markers that have been selected and that can help to carry out a 
more in-depth phenotyping of the study participants. This includes lifestyle 
questionnaires, liver fat and fibrosis grade, advanced lipoprotein profile, 
metabolites, and genetic markers; all of them have been widely used by our group 
in other studies. 
 
5.7.1 Main variables 
 
The six main variables to assess the outcome of the study are: age, anti-GAD 
antibodies, HbA1c, BMI, beta cell function (HOMA2-ß) and homeostatic model of 
insulin resistance assessment-2 (HOMA2-IR). These variables should allow the 
identification of the 5 relevant subgroups (clusters) of subjects initially described 
in the original study by Ahlqvist et al [25], ie SAID, severe autoimmune diabetes; 

 
 
 
 
 
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SIDD, severe insulin deficiency diabetes; SIRD, severe insulin-resistant diabetes; 
MOD, mild obesity-related diabetes; MARD, mild age-related diabetes. 
1. biomarkers: Antibodies against islet cell antigens (GADA65 and IA-2) will 
be measured with two commercially available ELISA kits: GAD65 
autoantibody ELISA and IA-2 autoantibody ELISA. The normal ranges of 
each local laboratory will be accepted. 
2. HOMA2-IR and HOMA2-ß will be calculated with a calculator from 
Diabetes Trials Unit, University of Oxford: HOMA Calculator . (Diabetes 
Care. 1998; 21: 2191-2; this calculator is also available at: 
https://www.dtu.ox.ac.uk/homacalculator/). 
3. C-peptide is the parameter used in previous studies on clusters in T2DM. 
C-Peptide will be determined using the CLIA Immunoassay Kit Procedure 
Analyzer High sensitivity direct chemiluminescent . 
 
5.7.2 Other relevant variables 
For a detailed description of sociodemographic variables and other relevant 
clinical variables (including clinical laboratory analysis), see Table 1. 
Liver damage biomarkers: liver damage biomarkers will complement the 
characterization of metabolic complications associated with T2DM. See the 
detailed description in Table 1. 
 
5.8 Specific sub-studies 
 
The current design will be leveraged to address additional questions to further 
expand the phenotypic, metabolic, and genetic characterization at the time of 
T2DM diagnosis. Taking advantage of our previous experience and the available 
resources, we include a proposal of sub- studies that are clearly feasible. These 
sub-studies will be carried out in all the participants of the main study, except for 
the sub-study on subclinical atherosclerosis, which will be carried out only in 
centers with availability of carotid and femoral ultrasound equipment (Research 
Unit of Lleida). 
 
 
 

 
 
 
 
 
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5.8.1 Sub-study on diet and physical activity 
 
We will assess physical activity and dietary pattern in all study subjects through 
validated questionnaires (see detailed description in Table 1) self-administered or 
by telephone.  
Physical activity: it will be evaluated using the International Physical Activity 
Questionnaire validated in Spain (IPAQ) short version [31]. The IPAQ short form 
contains 7 questions that assess four domains: leisure-time physical activity, home 
and garden activities, work-related physical activity, and transportation-related 
physical activity. The IPAQ short form asks about three specific types of activities 
performed in the four domains listed above; These are light-intensity activities like 
walking, moderate-intensity, and vigorous-intensity. 
The activity is classified as low, medium and high, according to the estimated 
energy expenditure with each activity. Activities with a metabolic equivalent task 
(MET) of 8 METs are classified as vigorous; moderate are those activities with an 
energy expenditure of 4 METs, and light are those activities with an energy 
expenditure of 3.3 METs, such as walking. Additionally, physical activity is 
classified as sedentary or active if study participants engage in some form of 
moderate physical activity for at least 30 minutes/day. 
Dietary pattern: adherence to the Mediterranean Diet will be evaluated with the 14-
item questionnaire (MEDAS) [32]. This questionnaire is an adaptation of the 
previously validated 9-item questionnaire [33], which is used in the control group 
of the PREDIMED-Plus study. It contains 12 questions about the frequency of 
food consumption, of which 2 questions are related to the habitual consumption of 
typical foods of the Spanish Mediterranean Diet. Each question is scored from 0 to 
1. Low adherence is defined as a MEDAS of less than 9 points, and high 
adherence with a MEDAS of 9 points or more. 
 
 
5.8.2 Sub-study on advanced lipoprotein profiling  
 
A serum sample will be used for analysis of the advanced lipoprotein profile ( 
Liposcale ®) by two-dimensional diffusion-ordered 1H-NMR spectroscopy 

 
 
 
 
 
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(DOSY) (J Lipid Res.2015 ;56: 737–46 ). This procedure evaluates lipid 
concentrations (i.e., triglycerides and cholesterol), the size and number of particles 
of 3 different classes of lipoproteins (VLDL, LDL, and HDL), as well as the 
number of particles of 9 subclasses (VLDL large, medium and small, LDL and 
HDL). A more detailed description of this methodology is available in our recent 
publication (Cardiovasc Diabetol 2020;19:126 ). 
 
5.8.3 Sub-study on subclinical carotid and femoral atherosclerosis 
 
The Lleida Research Unit will carry out a sub-study on the prevalence of 
subclinical carotid and femoral atherosclerosis (the expected recruitment in this 
health area is 509 participants). This sub-study is completely feasible since this 
research unit is already leading a large cohort study (ILERVAS) in the region. 
Researchers in this area have all the experience and resources necessary to carry 
out this sub-study. We estimate that a total of 15% of newly diagnosed subjects 
will already harbor established clinical cardiovascular disease. All other subjects 
will be invited to participate in this optional procedure. This will be done in a 
specific visit in the same CAP. Carotid and femoral ultrasound will be performed 
using B-mode ultrasound and color Doppler. The presence of atherosclerotic 
plaque will be assessed in ten vascular territories: internal artery, bulb and 
common carotid, common and superficial femoral arteries. Atheromatous plaque is 
defined as an intima media thickness ( cIMT ) >1.5 mm protruding into the lumen 
of the vessel, according to the ASE Consensus Statement (J Am Soc Echocardiogr. 
2008; 21: 93-111) and methodology in previous publications of the group (Palanca 
et al. Diabetol ; 2019 ;18:93 ). 
 
5.8.4 Sub-study on initial antidiabetic treatment and other diabetes-related 
therapies 
 
Given that our organization has access to all the data generated during routine 
practice, we will also evaluate the use of antidiabetic therapies in the treatment of 
diabetes at the onset, and we will be able to analyze the degree of adherence to 
current guidelines (Red GDPS T2DM Guide; 2018; Guidelines for harmonization 

 
 
 
 
 
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pharmacotherapy , CatSalut ; 2019). eCAP data will be extracted for each 
participant for the first 6 months after diagnosis. Data on the type of medication, 
prescription frequency, dispensing data will be recorded. In addition, we will also 
collect data on lipids and lipid-lowering treatment. 
 
5.8.5 Metabolomic and genetic sub-studies related to diabetes 
 
The metabolomic characteristics will provide us with a more complete 
physiological and genetic view of the disease through the profile of metabolites 
and genetic markers in blood and urine samples. Metabolomic markers will be 
analyzed (free methionine and methionine sulfoxide, MetOx-148/Met-148 ratio in 
apo-A1, NMR of circulating lipoproteins and glycoproteins, specifically 
parameters of LDL and VLDL particles, and circulating GlycA glycoproteins, and 
GlycB ) of T2DM and associated complications. Genetic characteristics that cause 
defects in insulin secretion, insulin action, or autoimmune destruction of ß cells 
will be analyzed. In case of clinical suspicion, possible dominant (eg HNF1A, 
HNF4A, GCK) or recessive (eg WFS1, INS, EIF2AK3) monogenic mutations will 
be studied, depending on the suspected clinical phenotype. 
 
Table 1. Study variables. 
 
Socio-demographic variables 
Variable 
Source 
Definition, (Value) 
Age 
eCAP * 
Main, (≥18) 
Sex 
eCAP * 
Others, (male/female) 
MEDEA Index 
SIDIAP/PARENTS * 
Others, (R, U, U1-U5) 
ABS 
eCAP * 
others, 
Education level 
eCAP * 
Others, (Illiteracy, No 
primary studies, Primary 
studies, Secondary 
studies, University 
studies) 
Toxic habits 

 
 
 
 
 
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tobacco use 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (Smoker, non-
smoker, ex-smoker) 
alcohol consumption 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (Risk consumer, 
non-consumer) 
drug use 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (Consumer, non-
consumer) 
Comorbidities 
diabetes type 
eCAP 
/ 
SIDIAP 
/ 
PADRIS * 
Main, (T2DM, DM1, 
Gestational, secondary, 
others, ICD10: E10.xx-
E13.xx, O24.xx) 
Time of evolution of 
diabetes 
eCAP * 
Main, (months) 
dyslipidemia 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (ICD10: E78.xx) 
Hypertension 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (ICD10: I10.xx, 
I12.xx, I13.xx, I15.xx) 
Peripheral arterial 
disease 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (ICD10: I70.xx, 
I73.xx) 
Heart failure 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (ICD10: I50.xx) 
ischemic heart disease 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (ICD10: I20.xx, 
I25.xx) 
stroke 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (ICD10: G45.xx, 
G46.xx, I63.xx, I69.xx) 
Liver disease (excluding 
steatosis) 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (ICD10: K70.xx, 
K71.xx, K72.xx, 
K73.xx,K74.xx,K75.xx, 
K77.XX) 
Steatosis hepatic 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (ICD10: K75.81, 
K76.XX) 
Renal insufficiency 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (ICD10: N17.xx, 
N18.XX, N19) 
acute pancreatitis 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (ICD10: K85.xx) 
diabetic nephropathy 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (ICD10: E11.2, 
N08.3, R80) 
Diabetic neuropathy 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (CIE10: E11.4, 
G59, G56, G62, G63, 
G90, G99) 
Diabetic retinopathy 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (CIE10: E11.4, 
G59, G56, G62, G63, 
G90, G99) 
Causes of Mortality 
eCAP 
/ 
SIDIAP 
/ 
PADRIS / INE** 
Others, (ICD10: R99), 
specific causes 
Exploration variables 
heart rate 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (EK401, [ batecs 
/min]) 

 
 
 
 
 
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BMI (Body Mass Index) 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (TT103 [ kgs 
/m2]) 
Abdominal perimeter 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (EL401-[cm]) 
Diastolic Blood Pressure 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, 
(EK202 
-
[mmHg]) 
Systolic Blood Pressure 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, 
(EK201 
-
[mmHg]) 
/ Weight 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (TT102 - [ kgs ]) 
Height / Size / Height 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (TT101 -[cm]) 
Clinical variables 
GADA65 
AI-2 
eCAP 
/ 
SIDIAP 
/ 
PADRIS * 
Principal 
C -peptide 
eCAP 
/ 
SIDIAP 
/ 
PADRIS * 
Principal 
Creatinine: Serum 
Creatinine / Creatinine / 
Creatinine Ion / 
Creatinemia 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, [ c.subst . (serum 
)] 
Filtrat (Estimated CKD-
EPI): Estimated 
Glomerular Filtration 
(CKD-EPI) 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others 
HDL Cholesterol: Serum 
HDL Cholesterol / HDL 
/ HDL-C 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, [ c.subst . (serum 
)] 
LDL Cholesterol: Serum 
LDL Cholesterol / LDL / 
/ LDL-C 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, [ c.subst . ( serum 
)] 
Cholesterol: Serum 
Cholesterol 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others ,[ c.subst . ( serum 
)] 
Triglyceride -: 
Triglycerides Serum / 
Triacylglycerols 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others ,[ c. Subst . ( 
serum )] 
Glycohemoglobin (a1c) -
: Glycosylated 
Hemoglobin / hba1c 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Principal , [ fr.subst .] 
TSH 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
 
Glucose -: Serum 
Glucose / 
Glycaemia/Glycaemia 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others ,[ c.subst . ( serum 
)] 
leukocytes 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, [ c.subst . ( serum 
)] 
red blood cells 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others ,[ c.subst . ( serum 
)] 
Ers (San)- 
Hemoglobin;c.massa 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, CI013 

 
 
 
 
 
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(CCMH) 
 
hematocrit 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
others, 
Medium corpuscular 
volume 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
others, 
Mean Corpuscular 
Hemoglobin 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
others, 
Red blood cell 
distribution width 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
others, 
platelets 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
others, 
mean platelet volume 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
others, 
neutrophils 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
others, 
lymphocytes 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
others, 
monocytes 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
others, 
eosinophils 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
others, 
Basophils 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
others, 
eosinophils 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
others, 
Basophils 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
others, 
 
 Urat ( serum ); 
c. subst . 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others , Q54485 
 
              To the 
girl aminotransferase ( 
serum ); c.cat. 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, Q02185 
 
Aspartate 
aminotransferase ( serum 
); c.cat  
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, Q07585 
To the girl 
aminotransferase 
(plasma); c.cat. 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others 
Gamma- 
glutamyltransferase 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others 
urine creatinine 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others 
Microalbuminuria 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others 
Albumin / Creatinine  
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others , [ quotient dough 
/subst. ( urine )] 
urine pH 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others 
urine density 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others 

 
 
 
 
 
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proteinuria 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others 
Glucosuria 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others 
Ketonuria 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others 
Bilirubin in urine 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others 
Hematuria 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others 
nitrites in urine 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others 
Urobilinogen urine 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others 
urine leukocytes 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
(Negative positive) 
Leukocyte concentration 
in urine 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others 
erythrocytes in urine 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others 
Liver fat index (FLI) 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others 
Liver Fibrosis Index 
(NFS) 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others 
FIB4 Index 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others 
HOMA2-IR 
HOMA2-ß 
eCAP 
/ 
SIDIAP 
/ 
PADRIS * 
Principal 
Variables Sub-study on diet and physical activity 
IPAQ 
Questionnaire 
Seven questions related 
to physical activity 
Activities with a 
metabolic equivalent 
task (MET) 
Questionnaire 
Physical activity 
mild, moderate and high 
Adherence to the 
Mediterranean Diet 
Questionnaire 
Contains 12 questions 
about the frequency of 
food consumption and 2 
questions 
about 
the 
consumption of typical 
foods 
of 
the 
Mediterranean Diet 
Variables Sub-study on advanced lipoprotein profile ( Liposcale ®) 
VLDL 
LDL 
HDL 
1H-NMR spectroscopy / 
(DOSY) 
biological samples 
the size and number 
VLDL large medium and 
small, 
LDL and HDL 
1H-NMR spectroscopy / 
(DOSY) 
biological samples 
number of particles of 9 
subclasses 

 
 
 
 
 
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GlycA , and GlycB 
1H-NMR spectroscopy / 
(DOSY) 
biological samples 
number of particles 
Variables Sub-study on subclinical carotid and femoral atherosclerosis 
B-mode and color Doppler ultrasound 
Carotid 
common 
drag < 50% 
eCAP /SIDIAP 
Altered / Normal 
Carotid 
common 
right > 50% 
eCAP / SIDIAP 
Altered / Normal 
Carotid common left 
<50% 
eCAP / SIDIAP 
Altered / Normal 
Carotid common left 
> 50% 
eCAP / SIDIAP 
Altered / Normal 
Bulb right <50% 
eCAP / SIDIAP 
Altered / Normal 
Bulb right > 50% 
eCAP / SIDIAP 
Altered / Normal 
Bulb left <50% 
eCAP / SIDIAP 
Altered / Normal 
Bulb left > 50% 
eCAP / SIDIAP 
Altered / Normal 
Right internal carotid 
<50% 
eCAP / SIDIAP 
Altered / Normal 
Right internal carotid 
artery > 50% 
eCAP / SIDIAP 
Altered / Normal 
Left internal carotid 
artery <50% 
eCAP / SIDIAP 
Altered / Normal 
Left internal carotid 
artery> 50% 
eCAP / SIDIAP 
Altered / Normal 
Right 
external 
carotid <50% 
eCAP / SIDIAP 
Altered / Normal 
Right 
external 
carotid artery > 50% 
eCAP / SIDIAP 
Altered / Normal 
carotid Left <50% 
eCAP / SIDIAP 
Altered / Normal 
carotid left> 50% 
eCAP / SIDIAP 
Altered / Normal 
Common 
femoral 
right 
eCAP / SIDIAP 
Altered / Normal 
Common 
femoral 
left handed 
eCAP / SIDIAP 
Altered / Normal 
Right 
superficial 
femoral 
eCAP / SIDIAP 
Altered / Normal 
Left 
superficial 
femoral 
eCAP / SIDIAP 
Altered / Normal 
Carotid 
right 
not 
valued 
eCAP / SIDIAP 
If not 
carotid not valued 
eCAP / SIDIAP 
If not 
Right femoral not 
valued 
eCAP / SIDIAP 
Otherwise 

 
 
 
 
 
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Femoral 
Left 
unfavorable 
eCAP /SIDIAP 
Otherwise 
Right intima-media 
thickness (IMT) 
eCAP /SIDIAP 
Value 
Left 
intima-media 
thickness (IMT) 
eCAP /SIDIAP 
Value 
Medium 
intima-
media 
thickness 
(IMT) 
eCAP /SIDIAP 
Value 
carotid plates 
eCAP /SIDIAP 
Number plates 
plate type 
eCAP /SIDIAP 
(Hypoechoic, 
Hyperechoic, Calcified) 
femoral plates 
eCAP /SIDIAP 
Number plates 
EA0 
eCAP /SIDIAP 
1 
EA2 
eCAP /SIDIAP 
3 
EA3 
eCAP /SIDIAP 
4 
Sub-study on initial antidiabetic treatment and other diabetes-related therapies 
Drugs antidiabetics 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (ATC/DDD: 
A10, dosage, frequency, 
dispensing) 
Lipid-lowering 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (ATC/DDD: 
C10, posology, 
frequency, dispensation) 
Antiaggregants 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (ATC/DDD: 
B01AC, posology, 
frequency, dispensation) 
Anticoagulants 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (ATC/DDD: 
B01AA, posology, 
frequency, dispensation) 
hypotensive 
eCAP 
/ 
SIDIAP 
/ 
PADRIS ** 
Others, (ATC/DDD: 
C07, posology, 
frequency, dispensation) 
Metabolomic and genetic sub-studies related to diabetes 
Metabolomics  
biological samples 
free methionine, 
methionine sulfoxide, 
MetOx-148/Met-148 
ratio, apo-A1 
Genetics  
biological samples 
HNF1A, HNF4A, GCK, 
WFS1, INS, EIF2AK3 
 
*Baseline, **Baseline and follow-up, eCAP : Clinical history 
 
 

 
 
 
 
 
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6 . DATA COLLECTION AND ANALYSIS 
6.1 Data collection schedule 
The study period is estimated to be 36 months (from January 1, 2022 to December 31, 
2024), although recruitment is expected in the first 24 months, and can be extended 
until the expected recruitment is achieved. However, these times may be modified by 
the deadlines of the administrative process of starting up the study or by the situation 
generated by the current COVID-19 pandemic. 
 
6.2 Source of information 
The source of information will in all cases be the patient's clinical history and the 
electronic Case Report Forms (eCRF) for the physical activity and diet questionnaires. 
 
6.2.1 Information collected 
 
This study proposes a prospective collection of information, that is, baseline data will 
be obtained in a single visit. The monitoring variables will be collected by linking with 
the SIDIAP/PADRIS databases. In the event that the link with the SIDIAP/PADRIS 
databases is not possible for technical reasons (non-ICS centers), the available 
monitoring variables will be collected from the electronic medical record. 
  
Next, all the variables that will be collected during the study visit and during follow-
up are described, as long as they are available in the patient's clinical history or can be 
obtained during the interview between the doctor and the patient during said visit. 
without applying any type of diagnostic or therapeutic intervention outside of routine 
clinical practice. 
 
The data will be collected by completing an ECRF (Annex 1), in order to record the 
information available in the patient's clinical history. The linking of patients with large 
SIDIAP/PADRIS databases will be carried out annually. The link will be made 
through the encrypted CIP (encrypted) of the patients included in the study that have 
allowed the data to be linked with the signed informed consent. The linking of the 

 
 
 
 
 
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encrypted CIPs with INE (specific causes of mortality) is managed through SIDIAP. 
The identification of the complications of T2DM, comorbidities and treatments will be 
carried out using the SIDIAP/PADRIS population databases, mainly where possible, 
which corresponds to the data of the registered clinical history of Primary Health Care 
in Catalonia. In the case of non-ICS centers, the collection of monitoring variables will 
be done directly from the clinical course of the participants. 
Table 2. Information collection scheme during the study. 
 
Information related to the 
patient  
Preselection 
Visit 
inclusion 
Tracing 
SIDIAP/PADRIS/INE/electronic 
clinical record 
Review of selection 
criteria 
x 
x 
 
Informed consent 
x 
x 
 
Data recording at 
study visit 
 
x 
 
Socio-demographic 
data a                              
 
 
 
Clinical datab                    
 
x 
x 
History of T2DM 
 
x 
 
Comorbidities of 
interest 
 
x 
x 
Specific mortality 
 
 
x 
Laboratory data c            
 
x 
x 
Smoking 
habit/alcohol/drug use 
 
x 
 
Pharmacological 
treatment                             
 
x 
x 
Diet and physical 
activity variables 
 
x 
 
Variable subclinical 
carotid and femoral 
atherosclerosis and 
 
x 
 
Biological samples 
 
x 
 
Variables advanced 
lipoprotein profile 
(Liposcale) f 
 
 
 
Metabolomic and 
genetic variables g 
 
 
 
 
to Age, sex, ABS, the MEDEA will be collected from SIDIAP/PADRIS 
b Weight, height, (auto calculated BMI), and abdominal circumference, SBP/DBP and heart rate 
c The laboratory parameters, the main variables will be collected during the inclusion visit, the rest of the laboratory parameters will be 
collected from SIDIAP/PADRIS 
d Treatment for inclusion will be collected at the visit and from the SIDIAP/PADRIS database Includes prescription, posology, dose 
e They will be collected at the inclusion visit only in centers that have equipment to assess atherosclerosis. 
f They will be collected at the end of the study, from the blood samples obtained at the inclusion visit 

 
 
 
 
 
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g They will be collected at the end of the study, from the blood/urine samples obtained at the inclusion visit. 
 
6.2.2 Recruitment procedure for possible candidates 
The health professional who sees for the first time a patient who meets the inclusion 
criteria and none of the exclusion criteria, will inform the principal investigator of the 
center (IPC) or the collaborating investigators (CI) with authorization to carry out this 
task. After that, the IPC/IC will make an appointment with the patient in a time not to 
exceed one week in order to obtain informed consent and include the patient in the 
study and, subsequently, proceed to physical examination, collection of history data, 
schedule the analytical study and collection of biological samples. All study 
procedures will be carried out only by the center's research team. 
 
6.3 Data analysis 
 
We will perform the cluster analysis (k- means and hierarchical clustering) following 
the method described by Ahlqvist et al [25]. New adult-onset diabetes subgroups and 
their association with outcomes: a cluster analysis based on six-variable data. Men and 
women will be grouped separately to avoid stratification due to sex-dependent 
differences in group variables. Continuous variables will be centered on the mean and 
standardized, and continuous variables greater than five standard deviations from the 
mean will be excluded; categorical variables will be included as binary variables. 
Two-step clustering will be used, in which the first step estimates the optimal number 
of clusters based on the width of the silhouette and the second step performs 
hierarchical clustering using the log probability as the distance measure and the 
Bayesian criterion of Schwarz for grouping. The stability of the groups will be 
evaluated by resampling the data set 2000 times, and calculating the Jaccard 
similarities with the original group. Generally, stable clusters should produce a Jaccard 
similarity greater than 0.75. Once the clusters are defined, we will assign the same 
names as in the original study based on the distribution of cluster features. We will 
assign each subject to their cluster according to their Euclidean distance from each 
cluster center. Differences between subtypes will be assessed by descriptive analysis 
and tested by Fisher's exact test, ANOVA test, and post hoc comparisons. A p value of 
less than 0.05 will be considered statistically significant in the phenotypic analyzes 

 
 
 
 
 
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and corrected for multiple comparisons. In addition, the Benjamini & Hochberg 
correction will be used to determine the significance of multiple tests (by variables). 
Statistical analysis will be performed using the R statistical software package (version 
> 3.6.3), and cluster analysis will be performed in the fpc (Flexible Procedures for 
Clustering) package, version > 2.2. 
 
6.4 Sample size 
 
This is a descriptive study without confirmatory analysis of a specific hypothesis. 
Therefore, the sample size has not been calculated according to an expected hypothesis 
or a specific measure of desirable association. Additionally, we have evaluated the 
number of subjects in previous studies similar to the current one in other countries 
(references 26 and 29, in Background); all used a similar approach with a sample size 
similar to or smaller than that proposed for this study. As stated above, we plan to 
recruit a total of 1,200 participants, spread across 11 centers over a 24-month 
recruitment period. This estimate has been based on an expected incidence of 4 T2D 
per 1000 person-years according to our own study in our population, as part of a recent 
international collaboration [34]. 
6.5 Limitations of the design, the source of information and the methods of 
analysis 
One of the limitations may be the relative representativeness of the participants 
included in this study. We opt for a realistic approach that allows us to develop an 
initial project that strikes the most appropriate balance between viability and sufficient 
representativeness. We believe that this proposal addresses this issue and may allow us 
to cooperate in this field with other national and international researchers. In fact, due 
to lack of time and limited funding for a call like the current one, we have not been 
able to undertake a large collaborative study in the country; however, we plan to 
approach other Spanish researchers in the field to complement our research with other 
regions of the country. 
Another limitation lies in the cluster analysis, which is an exploratory unsupervised 
analysis. It does not assume any underlying knowledge of the pathophysiology of the 

 
 
 
 
 
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condition and needs clinical interpretation. Some forms of cluster analysis may 
produce slightly different results each time the statistical analysis is run. 
 
 

 
 
 
 
 
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7. DATA HANDLING  
 
7.1 Data collection and confidentiality  
 
The data will be entered by the researchers themselves and/or authorized personnel 
directly in ECRF (Annex 1). In order to guarantee the confidentiality of the data 
obtained from the study, only the local researcher and his team of collaborators (after 
signing Annex 3), the sponsor or the person designated by him, the CEI will have 
access to them. , the relevant health authorities and those responsible for data analysis. 
 
Regarding the ECRF, each researcher will be given a username and a password made 
up of between 4 and 6 digits by means of a closed document. These codes are 
considered confidential and non-transferable, and are subject to the same 
confidentiality rules as the rest of the documents, including the protocol. It is the 
researchers' responsibility to keep their passwords secret and not to disclose them to 
third parties. To obtain access to the ECRF, the researchers must sign the study 
researcher commitment and confidentiality commitment ( Annex 3 ). 
 
The content of the ECRF, as well as the documents generated during the study and the 
database, will be protected from unauthorized use by people outside the research and, 
therefore, will be considered strictly confidential and will not be disclosed to third 
parties. In addition, the ECRF will be automatically disconnected in the case of lack of 
activity for more than 10 min, in this way the ECRF will be protected from the entry 
of unauthorized persons, in the event that for some reason the ECRF has been left 
open by the / the study researcher. 
 
The patients included in each center will have a correlative number (code), 
automatically generated by the ECRF once the informed consent has been signed and 
the inclusion criteria in the ECRF have been completed. This patient code will be 
documented in the participant's clinical record and in the confidential patient inclusion 
record in the investigators' folder of each participating center. The linking of patients 
with the SIDIAP/PADRIS databases will be carried out annually. The link will be 

 
 
 
 
 
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made through the encrypted CIP (encrypted) of the patients included in the study who 
have allowed the data to be linked with the signed informed consent. 
7.2 Mandatory requirements on the Data Protection Law regulation (EU) No. 
2016/679 and Organic Law 3/2018 Protection of Personal Data and digital rights 
guarantee (RGPD)   
 
7.2.1 Identification of the data and the subjects that treat them 
 
The variables necessary to carry out the study are those specified in the variables 
section ( Table 1 ), and will come from the participants/electronic medical record ( 
eCAP ) after obtaining informed consent and from the SIDIAP/PADRIS population 
databases such as it is specified in sections (5.3; 5.6; 5.7; 6.2; 7.1) The variables of the 
participants/electronic clinical record ( eCAP ) will be crossed with information from 
the SIDIAP/PADRIS population databases for the centers where possible (ICS) or it 
will be collected directly from the electronic medical record (Non-ICS centers). The 
information will be encrypted. Coding will be done through the ECRF as specified in 
section 7.1 Data collection and confidentiality. 
 
7.2.2 Identification of the treatments and legitimizing basis of the treatments 
 
The processing of personal data required in this study is governed by Organic Law 
3/2018, of December 5, on the protection of personal data. The Institute Català de la 
Salut acts as data controller within the framework of this study. The data finally 
registered in the central database will be the property of the promoter. The identity of 
the participants will not be revealed to any other person except the health authorities, 
when required or in cases of medical emergency. The Research Ethics Committees, 
the representatives of the Health Authority in matters of inspection and the personnel 
authorized by the Promoter, may only access to check the personal data, the clinical 
study procedures and compliance with the standards of good clinical practice. (always 
maintaining the confidentiality of the information). 
 

 
 
 
 
 
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The Researcher and the Promoter are obliged to keep the data collected for the study 
for at least 5 years after its completion. Subsequently, the personal information will 
only be kept by the patient's health center, and by the promoter for other scientific 
research purposes if the patient has given their consent to do so, and if permitted by 
applicable law and ethical requirements. 
 
The Information System for the Development of Research in Primary Care, 
(SIDIAP/PADRIS), managed by the IDIAP Jordi Gol i Gurina foundation, when 
crossing patient data, must have their data (CIPS) for the provision of the service, so it 
will act as the person in charge of the treatment. The project database will be hosted on 
the SIDIAP/PADRIS servers, for which it will act as data processor. 
 
The analysis of the coded data will be carried out in the research support units of 
Lleida and Barcelona. The final encrypted database without the possibility of 
identifying the subjects will be hosted on the servers of these units that comply with 
the Catalan Institute of Health data protection regulations. 
 
Legal basis of the treatment: RGPD: 6.1 a) the interested party gave their consent for 
the treatment of their personal data for one or more specific purposes. 
 
7.2.3 Tools used to process the data 
 
To carry out the project, the REDCAP platform will be used, hosted on the promoter's 
servers. Research Institute of the Hospital de la Santa Creu i Sant Pau, and which has 
the security measures determined by the institution. The data is stored on the local web 
server where the organization has installed the software and is therefore only 
accessible on computers that have a trusted connection via VPN and secure credentials 
(certificates, RSA keys, or complex passwords). A system has been incorporated so 
that only the application service can send the data to the back office, through a firewall 
that only allows requests from the application's IP addresses. The web server has the 
X- Frame - Options HTTP header configuration enabled with the value " same-origin " 
to prevent clickjacking attacks. 

 
 
 
 
 
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7.2.4 Procedure for linking data with SIDIAP/PADRIS  
The information registered in the SIDIAP/PADRIS databases is pseudonymized. For 
this study, a standardized procedure already established in SIDIAP/PADRIS will be 
used, which allows data to be crossed in a controlled and confidential manner. This 
procedure is also a technical and functional separation between the research team and 
those who participate in carrying out pseudonymization. Pseudonym data They will 
only be accessible to the research team according to the Guidelines established in 
Organic Law 3/2018, of December 5, on the Protection of Personal Data and the 
guarantee of digital rights. 
 
The procedure for comparing data from external sources with SIDIAP/PADRIS data is 
explained below: 
1. Research team encrypts the identifiers of the patients (CIP) who have given 
informed consent for linking the data through a password. 
2. Research team sends the data (encrypted identifier + variables) to the ICS (via 
SIDIAP/PADRIS) 
3. Research team sends the key to the ICS (via SIDIAP/PADRIS) 
4. The ICS decrypts the ECAP patient identifier with the investigator team's key 
5. ICS links information 
6. The ICS exchanges the encrypted identifier of the external source for the 
SIDIAP/PADRIS identifier 
7. The ICS sends the data to SIDIAP/PADRIS 
8. SIDIAP/PADRIS sends the data to the research team 
 
*The data crossing for specific mortality with INE is managed in the same way 
through SIDIAP. 
7.2.5 International data transfers 
 
Similar studies have been carried out in other countries, such as Sweden, Germany, 
UK [25,26]. It is possible that our group conducts collaborative studies with other 
national and international research groups related to diabetes. In no case, raw and 

 
 
 
 
 
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confidential data of the participants will be sent. International transfers will be made as 
regulated in chapter V of the RGPD (article 44, 45, 46 and 49 a: the interested party 
has explicitly given their consent to the proposed transfer, after having been informed 
of the possible risks for them of said transfers). transfers due to the absence of an 
adequacy decision and adequate guarantees). The transfer of data from our study 
would only be for patients who have accepted this option in the informed consent. If 
we transfer the encrypted data within the EU to the entities of our group, to service 
providers or to scientific researchers who collaborate with us, the participant's data 
will be protected with safeguards such as contracts or other mechanisms by the data 
protection authorities. data. 
7.2.6 Identification of treatments that may pose a high risk to the rights and 
freedoms of the participants in the research project. 
In accordance with the provisions of article 35 of the RGPD, the project does not meet 
the necessary characteristics that require the corresponding impact assessment to be 
carried out. As secondary objectives, it is planned to study the genetic factors related 
to diabetes mellitus, in order to better characterize the disease, the data will be coded. 
However, the impact assessment related to data protection for research projects and 
clinical innovation in health is attached in Annex 9, it has been evaluated as low risk. 
 
 7.2.7 Rights of interested persons 
 
In accordance with regulation (EU) No. 2016/679 and Organic Law 3/2018 Protection 
of Personal Data and digital rights guarantee, the patient can limit the processing of 
data that is incorrect, request a copy or transfer it to a third party (portability) the data 
you have provided for the study. To exercise these rights, you will contact the main 
researcher, the researchers at the study site or the Data Protection Delegate of the 
center as long as this figure exists in the center or promoter Institut de Recerca de 
l'Hospital de la Santa Creu i Sant Pau – IIB Sant Pau Sant Quintí , 89, 08041 
Barcelona, Tel: 93 553 78 69, email dpo_ir@santpau.cat , or with the Spanish Data 
Protection Agency at Jorge Juan, 6, 28001 Madrid (https: // www .aepd.es / es) or the 
Catalan Dades Protection Authority ( https://apdcat.gencat.cat ). 

 
 
 
 
 
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If the participant wants to know more about it, they can contact the Data Protection 
Delegate of the institution or the promoter Institut de Recerca de l'Hospital de la Santa 
Creu i Sant Pau – IIB Sant Pau Sant Quintí , 89, 08041 Barcelona, Tel: 93 5537869, 
email dpd@santpau.cat, or with the Spanish Data Protection Agency at Jorge Juan, 6, 
28001 Madrid (https: // www .aepd.es/es) or the Catalan Data Protection Authority 
(https://apdcat.gencat.cat). 
7.2.8 Data validation and quality control 
 
All data received through the use of the ECRF will be stored, and will be subjected to 
the appropriate work procedures to comply with the FDA 21 ECRF standard. Part 11 
guaranteeing, therefore, their confidentiality, security and authenticity. 
The adaptation of the 21 CFRe standard Part 11 ensures that data received via 
electronic transmission is as valid as originals received on paper. Said standard sets the 
rules for the use of electronic data and defines the requirements of all systems for their 
collection, storage, maintenance and security. 
 
All the data registered by the researcher in the system will be submitted to an 
automatic validation program that will review them and, accordingly, discrepancy 
reports will be generated to facilitate the correct and complete registration of the data 
(automatic queries). In addition, the data entered will be reviewed and verified by the 
study monitor. The corrections of the ECRF will be made by the researchers 
themselves. Raw data should be available and ready for review during scheduled 
monitoring visits. 
 
Likewise, all the documents of this study must be available to the duly qualified 
personnel responsible for the development of the audits or inspections that, if they 
occur, are carried out. The verification of the ECRF data must be carried out by direct 
inspection of the original documents. 
 
 

 
 
 
 
 
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Biological samples 
Collection and use 
 
The samples obtained will be labeled with a code to maintain confidentiality and will 
initially be processed by the Biobank IRBLleida and the Vall University Hospital 
Biobank d'Hebron (HUVH Biobank). At the end of the study they will be deposited in 
the Biobank – IIB Sant Pau. 
 
Responsible for data processing 
 
Biobank Sant Pau Biomedical Research Institute 
Santa Cruz and San Pablo Hospital Research Institute Foundation (hereinafter, 
FIRHSCSP or Foundation). Registered office: Calle San Antonio María Claret, 167, 
08025 Barcelona. Registered in the Registry of Foundations of the Government of 
Catalonia, with number 708. CIF: G-60136934. Telephone: 93.553.76.13. Contact 
email: biobanc@santpau.cat . 
Promoter: The principal investigator (Dr. Dídac Mauricio DNI: 46525502K) of the 
study and the Promoter - Research Institute of the Hospital de la Santa Creu i Sant Pau 
- IIB Sant Pau, c / Sant Antoni Maria Claret, 167 08025 Barcelona, Tel: 93 553 78 69. 
Contact email: dmauricio@santpau.cat  
 
Purposes 
Your data will be processed solely to carry out research to advance knowledge of 
diabetes (advanced lipo -protein profile, metabolomics and genetics sub studies). 
 
Legal basis of the treatment 
RGPD: 6.1 a) the interested party gave their consent to the processing of their personal 
data for one or more specific purposes. 
 
Rights of interested persons 
The same rights specified in point: 7.2.7 
 
 
 

 
 
 
 
 
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8 . WORK PLAN (tasks, milestones and study timeline): 
Month -2 
Participating centers: IR-HSCSP, CAPs of Lleida and Barcelona, USR Barcelona and 
Lleida, 
Meeting of the researchers for the coordination and resolution of doubts. Preparation 
of the logistical aspects for the start-up of the study (month -2). 
 
IR-HSCSP 
Presentation to CEIC (months -2, -1). 
 
1 months 
Participating centers: IR-HSCSP, CAPs of Lleida and Barcelona, USR Barcelona and 
Lleida, 
Inception visits with participating centers 
 
Months 1-24 
Participating centers: CAPs of Lleida and Barcelona, USR Barcelona and Lleida, 
Recruitment of participants 
 
Months 4, 8, 12, 16, 20, 24 
Participating centers: IR-HSCSP, USR Barcelona and Lleida 
Data monitoring 
 
Months 1-24 
Participating Centers: IR-HSCSP 
Collection of biological samples in Biobank  
 
Months 14,15,16,27,28,29  
Participating centers: USR of Barcelona 
Data management and linkage with SIDIAP/PADRIS databases 
 
 

 
 
 
 
 
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Months 17-20, 30-33 
Analysis of data 
Months 22-24, 34-36 
Participating centers: IR-HSCSP, USR Barcelona and Lleida, 
Elaboration of the report for the data collected during 2 years 
Interpretation and discussion of the results 
Preparation of communications and manuscripts 
Researchers meeting to discuss the results and close the study. 
 
 

 
 
 
 
 
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9 . ETHICAL ASPECTS: 
The present study complies with all the ethical aspects and protection of the 
participating subjects by complying with the ethical precepts formulated in Royal 
Decree 957/2020 and the Biomedical Research Law 14/2007, of July 3, and in the 
Declaration of Helsinki and all your reviews. 
 
Since this study is observational in nature, patient participation is considered to carry 
minimal risk; that is, the risk is similar to that which the patient would have in clinical 
practice without mediating their participation in the study. It is an unconditional 
prerequisite for the participation of a patient to obtain his consent after having been 
informed by the researcher about it both verbally and in writing in a vocabulary that 
allows its content to be completely readable and understandable for the patient (Annex 
5). 
 
The protocol will be submitted to the evaluation of a CEI prior to the start of the 
inclusion of the patients. Any data required by the protocol may be subject to audits by 
the promoter, independent organizations and/or competent authorities, but the 
confidentiality of the data in accordance with the aforementioned law will always be 
an essential condition. 
 
The participating subject may at any time revoke their consent for the use of their data 
in the analysis, without giving cause and without this resulting in any liability or 
damage whatsoever. 
 
Before accepting and signing the investigator's commitment, the participating clinical 
investigators must ensure that their participation in the study does not interfere with 
their prescription habits or their care duties. 
 
 
 

 
 
 
 
 
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9 .1 Benefit-risk assessment of the research 
This project affects the priority of developing personalized medicine. This project 
adopts a research approach that is clearly aimed at improving clinical decision-making 
that affects the people we serve. The potential impact may be equivalent to that 
mentioned for diabetes itself. 
The patient will not suffer any risk in this study since it is completely observational 
and, therefore, will not be subjected to any intervention, neither dietary nor 
pharmacological treatment. The present study is limited to an anonymized data record 
in a database that does not allow access to the patient's personal data. 
 
9.2 Ethical considerations, regarding information to subjects and informed 
consent 
The study will be carried out strictly following the international ethical 
recommendations for medical research in humans. The investigator will be responsible 
for ensuring that the study is carried out in accordance with the standards set out in the 
Declaration of Helsinki. 
Before starting the study, the Ethics Committee of the Hospital de la Santa Creu i Sant 
Pau must approve the study protocol, the information that will be given to the subject 
and the model of informed consent that will be used. 
For linking with the SIDIAP/PADRIS databases and carrying out the study in the 
primary care centers of the Institut Català de la Salut - ICS, the study will be evaluated 
by the Jordi Gol y Gurina IDIAP Scientific and Ethics Committee. 
For centers that have other reference RECs different from those previously mentioned, 
before starting recruitment in these centers, if necessary, the protocol will be passed 
for evaluation and approval by the corresponding reference RECs for these centers. 
The REC will be informed of any subsequent amendments to the protocol and its 
opinion should be sought if a new evaluation of the ethical aspects of the study is 
necessary. 
It is the investigator's responsibility to obtain informed consent from the patient. The 
patient will not be able to participate in any specific procedure of the study before 
obtaining their consent, or that of their legal guardian/relative when the patient is not 
capable of giving their consent due to their clinical situation. 

 
 
 
 
 
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Before including any subject in the study and before obtaining informed consent, the 
researcher or the person designated by the researcher will explain to the potential 
participating subject or their legal guardian/relative, the objectives, methods and 
potential risks of the study and any inconvenience it may cause. The explanation about 
the nature, scope and possible consequences of the study will be made in an 
understandable language. The rights related to the data protection law will be 
explained, as well as the possibility of being contacted in the case of future studies 
related to diabetes. 
The potential participating subject or their legal guardian/relative must have time to 
consider their decision to participate in the study, and have the opportunity to ask 
questions. After this explanation, and before entering the study, the consent must be 
properly recorded by the signature of the subject or their legal guardian/relative. The 
informed consent will be signed in three copies, one for the participant, another for the 
researcher and the third copy for the biobank. 
9.3 Considerations on the treatment of biological samples 
Regarding the obtaining, handling, identification and storage of biological samples, 
the provisions of the Biomedical Research Law 14/2007, of July 3, specifically in 
chapters III and IV of title V, as well as provided in Royal Decree 1716/2011, of 
November 18, specifically in chapter I of title II, which establishes the treatment of 
biological samples of human origin for biomedical research purposes. 
In accordance with said regulations, the obtaining of biological samples for biomedical 
research purposes may only be carried out when the prior written consent of the source 
subject has been obtained and prior information on the consequences and risks that 
such obtaining may entail for their health. Said consent will be revocable. The 
participants will be asked in the same informed consent for the study samples, also the 
use of the samples related to other future diabetes studies and other future non-diabetes 
related studies. 
The biological samples of the study will be processed by the Biobank IRBLleida and 
the Vall University Hospital Biobank d'Hebron ( HUVH Biobank ) at the end of the 
study will be stored by the Biobank – IIB Sant Pau. 
 

 
 
 
 
 
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9.3 Confidentiality of data 
 Regarding the confidentiality of the study data, the provisions of Organic Law 3/2018, 
of December 5, on the Protection of Personal Data and Guarantee of Digital Rights 
and the General Data Protection Regulation (EU) will be followed. 2016/679. 
 
9.4 Interference with the physician's prescribing habits 
 
The study will not interfere with the clinical management habits of patients 
10. PLANS FOR DISSEMINATION OF RESULTS: 
It is expected that, from the second year of the project, the results generated will be 
presented at national and international congresses that are benchmarks in diabetes 
research, such as the congresses of the Spanish Diabetes Society and the European 
Diabetes Society, or other societies (from the second year). 
In addition, it is expected that a scientific article will be published for each 
objective of the study in high-impact journals in the field. 
11. RESOURCES FOR CONDUCTING THE STUDY   
 
The research group has members with extensive experience in clinical 
research. They have led several projects, similar to the current one in terms of 
organizational and logistical capabilities, which have given rise to multiple 
publications. We will only mention a few of the studies that require similar 
knowledge, experience, and skills to that required for this proposal: D. Mauricio led a 
prediabetes cohort study (the Mollerussa cohort recruited more than 600 individuals 
and has already produced multiple publications; see publications of D. Mauricio); J. 
Franch led the PREDAPS study (Medicine; 2015;94:44); C. Farràs , leads the 
ILERVAS cohort study, in which J. Franch and D. Mauricio are also researchers 
(more than 8,000 people recruited PCC in the province of Lleida) ( Nefrologia . 
2016;36:389-396); D. Mauricio led a pragmatic trial (INTEGRA) in different CAPs in 
the territories of Barcelona, Lleida and Girona (more than 600 subjects included; 
Molló et al. BMC Family Practice 2019 ;20:25 ). M. Hernández and D. Mauricio 
recruited the Action LADA international collaborative Spanish cohort (this has 

 
 
 
 
 
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resulted in previous publications; see background section). Therefore, the previous 
experience and knowledge of the research team in the implementation of this type of 
study ensure that the project will be conducted successfully. 
Ultrasound: USR Lleida researchers (C. Farràs ), as well as the PI, have solid 
experience in the characterization and interpretation of subclinical atherosclerosis by 
vascular ultrasound. The Principal Investigator has contributed to several articles on 
clinical research on atherosclerosis in diabetes. 
USR (Primary Care Research Support Unit) Barcelona: J. Franch-Nadal (JF) is PI of 
the leading Epidemiological Research Group in Diabetes from Primary Care 
(DAPCAT). He has a long experience in conducting clinical research in the study of 
diabetes in primary health care through epidemiological studies based on the 
exhaustive analysis of routinely collected data. B. Vlacho (BV) is a project manager 
expert in managing clinical research projects. Other members of the team are those of 
each CAP: B. Ribas (BR), a family doctor with experience in clinical research, has 
been participating as an investigator in different trials and a project financed by the 
ISCIII (ITADI study). Ana M. Pedro Pijoan (AM.PP) family doctor and clinical 
researcher with experience Dos de Maig /ABS Gaudí. N. Riera (NR), experienced 
family physician and clinical research investigator, involved in intervention programs 
to improve medical care. C.González -Blanco (CG-B) medical endocrinologist 
Hospital Dos de Maig . H. Hernández Boluda (HH), experienced family physician and 
site investigator. He participated as a site investigator in the INTEGRA study. 
USR Lleida: M. Ortega (MO), family doctor specializing in primary care therapeutics, 
and coordinator of the Primary Care Therapies Research Group (GRETAP). His team 
includes E. Artigues (EA), J. Sol (JS), L. Azlor (LA), and JI Garcia (JIG). E. Artigues 
is a nurse doctor specializing in health education, and an expert in community care and 
health promotion. J.Sol is a predoctoral researcher in biomarkers metabolomics and 
lipidomics . L. Azlor has a master's degree and is an expert in Biostatistics. JI. García 
is a pharmacist with a specialization in Hospital Pharmacy and a Master's degree in 
Clinical Research, Psychopharmacology and Aging. Other members of the team are 
those of each PCC: J. Pujol (JP), family doctor with experience in clinical trials (as PI 
in 3 trials) with a special interest in diabetes research. M. Solanes (MS), family doctor 
and field researcher in the two intervention trials (INTEGRA and E-COVID), and as 

 
 
 
 
 
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principal investigator in two projects (ECOGRAFIES Lleida and Ultrasound in 
primary care) A. Lafarga (AL) : family doctor and researcher trained at the clinical 
center, participated in the INTEGRA study. S. Guerrero (SG), family doctor and 
highly motivated researcher in diabetes research (different local studies). M. Marin 
(MM), family doctor; Over the years, he participated in a local intervention study to 
improve diabetes care. 
Additionally, the sub -study on preclinical atherosclerosis that will take place in the 
health area of Lleida (6 CAP; half of the study participants) will be carried out without 
problems since the USR Lleida already has the stage to carry out the study without 
additional resources, since which are already running the second wave of the 
ILERVAS study. 
 
The study is funded by the Carlos III Health Institute (FIS 2020 PI21/01163). 
12. CHANGES TO THE PROTOCOL: 
Any modification of the study protocol will always take the form of a written 
amendment or addendum. For its formalization, the approval of all the people 
responsible for the study will be required. In the case of relevant modifications, the 
express approval of the Clinical Research Ethics Committee will be requested. 
 
 

 
 
 
 
 
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1 3. PRACTICAL CONSIDERATIONS: 
 
Start, follow-up and end reports 
The start of the study will be notified to the ethics committee. Subsequently, annual 
monitoring reports will be sent. After obtaining the conclusions of the study, a final 
report will be prepared and presented to the ethics committee. 
 
14. BIBLIOGRAPHY: 
[1] Busse et al.Tackling chronic disease in Europe: strategies, interventions and 
challenges, WHO Regional Office Europe, 2010.  
[2] F. Soriguer, A. et al.Revalence of diabetes mellitus and impaired glucose 
regulation in Spain: the Di@ bet. es Study, Diabetologia. 55 (2012) 88 -93.  
[3] Mauricio et al. Chronic Diabetes Complications: The Need to Move beyond 
Classical Concepts, Trends Endocrinol. Metab. 31 (2020) 287 -295. 
https://doi.org/10.1016/j.tem.2020.01.007.  
[4] Hurtado et al. What is type 2 diabetes?, Medicine (Baltimore). 47 (2019) 10 -15.  
[5] Pearson et al. Lecture 2013 Stratified approaches to the management of diabetes, 
Diabet. Med. 31 (2014) 393 -398.  
[6] Mata-Cases et al. Clinical inertia in the treatment of hyperglycemia in type 2 
diabetes patients in primary care, Curr. Med. Res. Opin. 29 (2013) 1495 -1502. 
https://doi.org/10.1185/03007995.2013.833089.   
[7] Mata-Cases et al. Glycaemic control and antidiabetic treatment trends in primary 
care centres in patients with type 2 diabetes mellitus during 2007 -2013 in Catalonia: a 
population-based study, BMJ Open. 6 (2016) e012463. 
https://doi.org/10.1136/bmjopen-2016-012463.  
[8]  Blind et al. The European Medicines Agency's approval of new medicines for type 
2 diabetes, Diabetes, Obes. Metab. 20 (2018) 2059 -2063. 
https://doi.org/10.1111/dom.13349.   
[9] Hernández et al. Latent Autoimmune Diabetes in Adults: A Review of Clinically 
Relevant Issues, in: Diabetes from Res. to Clin. Pract. Vol. 4, Springer, 2020: pp. 29 -
41. https://doi.org/10.1007/5584_2020_533.   

 
 
 
 
 
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[10] Castelblanco et al. Low-grade Inflammatory Marker Profile May Help to 
Differentiate Patients With LADA, Classic Adult-Onset Type 1 Diabetes, and Type 2 
Diabetes, Diabetes Care. 41 (2018) 862 -868. https://doi.org/10.2337/dc17-1662.  
[11] Hernández et al. Preclinical carotid atherosclerosis in patients with latent 
autoimmune diabetes in adults (LADA), type 2 diabetes and classical type 1 diabetes, 
Cardiovasc. Diabetol. 16 (2017) 94. https://doi.org/10.1186/s12933-017-0576-9.   
[12] Mollo et al. Latent autoimmune diabetes in adults is perched between type 1 and 
type 2: evidence from adults in one region of Spain, Diabetes. Metab. Res. Rev. 29 
(2013) 446 -451. https://doi.org/10.1002/dmrr.2411.   
[13] Hawa et al. Metabolic Syndrome and Autoimmune Diabetes: Action LADA 3, 
Diabetes Care. 32 (2009) 160 -164. https://doi.org/10.2337/dc08-1419.   
[14] Hawa et al. Adult-Onset Autoimmune Diabetes in Europe Is Prevalent With a 
Broad Clinical Phenotype: Action LADA 7, Diabetes Care. 36 (2013) 908 -913. 
https://doi.org/10.2337/dc12-0931.  
[15] Mishra et al. Relative contribution of type 1 and type 2 diabetes loci to the genetic 
etiology of adult-onset, non-insulin-requiring autoimmune diabetes, BMC Med. 15 
(2017) 88. https://doi.org/10.1186/s12916-017-0846-0.  
[16] Mishra et al. Genetic Discrimination Between LADA and Childhood-Onset Type 
1 Diabetes Within the MHC, Diabetes Care. 43 (2020) 418 -425. 
https://doi.org/10.2337/dc19-0986.  
[17] ADA, Introduction: Standards of Medical Care in Diabetes --2021, Diabetes Care. 
44 (2021) S1 -S2.  
[18] WHO, Classification of diabetes mellitus, WHO, 2019. 
https://www.who.int/health-topics/diabetes#tab=tab_1.  
[19] Buzzetti et al. Management of Latent Autoimmune Diabetes in Adults: A 
Consensus Statement From an International Expert Panel, Diabetes. 69 (2020) 2037 -
2047. https://doi.org/10.2337/dbi20-0017.   
[20] Fitipaldi et al. Global Overview of Precision Medicine in Type 2 Diabetes, 
Diabetes. 67 (2018) 1911 -1922. https://doi.org/10.2337/dbi17-0045.   
[21] Chung et al. Precision Medicine in Diabetes: A Consensus Report From the 
American Diabetes Association (ADA) and the European Association for the Study of 

 
 
 
 
 
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Diabetes (EASD), Diabetes Care. 43 (2020) 1617 -1635. 
https://doi.org/10.2337/dci20-0022.   
[22] Prasad et al. Precision medicine in type 2 diabetes, J. Intern. Med. 285 (2019) 40 -
48. https://doi.org/10.1111/joim.12859.   
[23] McCarthy, Painting a new picture of personalised medicine for diabetes, 
Diabetologia. 60 (2017) 793 -799. https://doi.org/10.1007/s00125-017-4210-x.  
[24]Udler et al. Genetic Risk Scores for Diabetes Diagnosis and Precision Medicine, 
Endocr. Rev. 40 (2019) 1500 -1520. https://doi.org/10.1210/er.2019-00088.   
[25] Ahlqvist et al.  Novel subgroups of adult-onset diabetes and their association with 
outcomes: a data-driven cluster analysis of six variables, Lancet Diabetes Endocrinol. 
6 (2018) 361 -369. https://doi.org/10.1016/S2213-8587(18)30051-2. 
[26] Zaharia et al. Risk of diabetes-associated diseases in subgroups of patients with 
recent-onset diabetes: a 5-year follow-up study, Lancet Diabetes Endocrinol. 7 (2019) 
684 -694. https://doi.org/10.1016/S2213-8587(19)30187-1.   
[27] Wagner et al.  Pathophysiology-based subphenotyping of individuals at elevated 
risk for type 2 diabetes, Nat. Med. 27 (2021) 49 -57. https://doi.org/10.1038/s41591-
020-1116-9.  
[28] Dennis et al. Disease progression and treatment response in data-driven 
subgroups of type 2 diabetes compared with models based on simple clinical features: 
an analysis using clinical trial data, Lancet Diabetes Endocrinol. 7 (2019) 442 -451. 
https://doi.org/10.1016/S2213-8587(19)30087-7.  
[29] Bello-Chavolla et al. Clinical characterization of data-driven diabetes subgroups 
in Mexicans using a reproducible machine learning approach, BMJ Open Diabetes 
Res.  
[30] Udler et al. Type 2 diabetes genetic loci informed by multi-trait associations point 
to disease mechanisms and subtypes. A soft clustering analysis, PLOS Med. 15 (2018) 
e1002654. https://doi.org/10.1371/journal.pmed.1002654. 
[31]. Román Viñas B, Ribas Barba L, Ngo J, Serra Majem L. Validation in the Catalan 
population of the international physical activity questionnaire [ Validity of the 
international fitness activity questionnaire in the Catalan population ( Spain )]. gac 
Sanit . 2013 May-June ;27 (3):254-7. Spanish. doi : 10.1016/j.gaceta.2012.05.013. 
Epub 2012 Oct 24. PMID: 23103093. 

 
 
 
 
 
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[32] Schröder H, Fitó M, Estruch R, Martínez-González MA, Corella D, Salas- 
Salvadó J, Lamuela -Raventós R, Ros E, Salaverría I, Fiol M, Lapetra J, Vinyoles E, 
Gómez-Gracia E, Lahoz C, Serra- Majem L, Pintó X, Ruiz- Gutierrez V, Covas MI. A 
short screener is valid for assessing Mediterranean diet adherence among older 
Spanish men and women. J Nutr . 2011 Jun ; 141 (6): 1140-5. doi : 10.3945 / 
jn.110.135566. Epub 2011 Apr 20. PMID: 21508208. 
[33] Martínez-González MA, Fernández-Jarne E, Serrano-Martínez M, Wright M, 
Gomez-Gracia E. Development of a short dietary intake questionnaire for the 
quantitative estimation of adherence to a cardioprotective Mediterranean diet. Eur J 
Clin Nutr. 2004;58:1550–2. 
[34]  Magliano DJ, Chen L, Islam RM, Carstensen B, Gregg EW, Pavkov ME, Andes 
LJ, Balicer R, Baviera M, Boersma-van Dam E, et al. Trends in the incidence of 
diagnosed diabetes: a multicountry analysis of aggregate data from 22 million 
diagnoses in high-income and middle-income settings. Lancet Diabetes Endocrinol 
(2021) 9:203–211. doi:10.1016/S2213-8587(20)30402-2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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15. EXPERIENCE OF THE RESEARCH TEAM  
 
The research team is made up of professionals from different disciplines, a good part 
of whom have been collaborating for a number of years in this area of research. 
D. Mauricio leads the Diabetes Research Group of this institution (HSCSP-IR), which 
belongs to the CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), 
Carlos III Health Institute (ISCIII). He has published more than 240 peer-reviewed 
articles (H-index: 42), mainly in the field of diabetes. He has extensive experience in 
clinical studies in diabetes, having participated in multiple national and international 
research initiatives such as PI. He has been funded by the Carlos III Health Institute, 
and international research organizations, leading 8 projects as PI in the last 10 years. 
The main research activities focus on the study and treatment of diabetes and its 
associated complications, and also on the evidence in real practice (see below). 
J. Franch is a family doctor and principal investigator of the DAP-CAT group, heading 
the Epidemiological Research Group on Diabetes from Primary Care (IDIAP Jordi 
Gol Research Institute). He is a national primary care expert and leader in the field of 
type 2 diabetes. He has long experience conducting clinical research on diabetes in 
primary health care through epidemiological studies. In 2009, D. Mauricio and J. 
Franch pioneered clinical evidence research in real practice using large database 
epidemiology studies in the field of diabetes. Together, they have also conducted 
pragmatic primary care trials. J. Franch will be instrumental in leading the project at 
the primary care level. 
The research team also includes experience in the field of endocrinology in both 
participating territories. M. Hernández (Lleida) and C. González (Barcelona) will 
contribute their experience in this field. M. Hernández will contribute with his 
experience in the field of LADA, and C. González will be essential for his experience 
in technology in diabetes and communication with patients. 
Fortunately, we have been able to gather the necessary experience and commitment 
from the 2 IDIAP Research Support units involved in Lleida and Barcelona, where the 
relevant leadership is provided by local leaders M. Ortega and J. Franch, respectively. 
M. Ortega coordinates research initiatives in primary care in the health area of Lleida, 
with extensive experience in interventional studies in CPCs in this region. Relevant 

 
 
 
 
 
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experience and key members of the local teams are outlined in the section on 
Available Resources. 
The proven national and international leadership of different members in clinical 
diabetes has resulted in participation in guidelines from different scientific 
organizations: Primay Care Diabetes Europe ( J. Franch ; Prim Care Diabetes. 2021 
;15: 31-51); redGDPS in Spain (J. Franch; Diabetes Practice. 2020;11:117-162 and 
Diabetes Practice. 2020;11:47-54); International group of experts in LADA (D. 
Mauricio; Diabetes. 2020;69:2037-2047); 
The team includes 1 senior statistician and collaborators from the statistical team of 
the USR units. J. Real is a senior data scientist, with more than 13 years of experience 
in data management and statistical analysis of large population databases. In addition, 
the bioinformatics group of Dr. Perera (UPC, Univ. Politècnica de Catalunya) will 
advise and support these analyses. 
Two members of the team (M. Granado, RD and PhD, and K. Rodríguez, RD, MD) 
will lead the lifestyle studies. Together with the main researcher, M. Granado, M. 
Mata and J. Franch have carried out several studies in this field. 
Finally, we want to highlight the fact that the key researchers of this project are 
members of the CIBERDEM research group led by D. Mauricio: J. Franch, J. Real and 
M. Granado. This group has achieved excellence among the 31 CIBERDEM groups, 
having reached the first and second position in the annual evaluations of 2018 and 
2019, respectively. Our research group has stable and ongoing collaborations with 
other international researchers: Kamlesh Khunti (University of Leicester, UK) and 
Dianna Magliano ( Monash University , Melbourne, AUT) in the field of real world 
data and diabetes epidemiology; Angelo Avogaro (University of Padova , IT), Peter 
Rossing ( Steno Diabetes Center, DK) and Per- Henrik Group (University of Helsinki, 
FI) in the field of diabetes complications. 
 
 
 

 
 
 
 
 
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16. APPLICABILITY OF THE PROJECT 
This project entails the application of research in different priority areas defined in the 
current AES call. 
Capacity of the project to address the objectives and priorities of the Social Challenge 
of Health, Demographic Change and Well-being of the Spanish Strategy for Science, 
Technology and Innovation. 
This project addresses important questions about the current objectives and priorities 
of the Spanish investigative authority. First of all, the study focuses on a relevant 
health problem, that is, diabetes mellitus. Actually, type 2 diabetes mellitus is one of 
the main causes of morbidity and mortality in our country and the prevalence of the 
disease is growing more and more to an epidemic proportion as in other developed 
countries. Second, the project is an effort on precision medicine in diabetes. This is 
also considered a priority both locally and internationally. The project focuses on 
precision diagnosis, as a first step towards the implementation of other aspects of 
precision medicine (prevention, prognosis, therapeutics, follow-up). Individualization 
and shared decision making are now at the center of diabetes care; however, the 
optimal distribution of these important aspects of clinical care must be based on the 
integrity of the relevant information (in this case, deep phenotyping). Therefore, 
precision medicine in diabetes is a requirement for optimal individualization and 
decision-making. 
  
translational research proposal 
The findings of the current project should result in a simple application to develop new 
strategies for an improvement in the diagnostic approach of T2DM (accuracy 
diagnosis). In addition, the proposed cohort is the basis for future projects in the field 
of precision medicine in diabetes. In fact, the follow-up of the prospective cohort will 
provide very relevant information on the prognosis of the disease (precision 
prognosis), the prevention of complications (precision prevention) and, more 
importantly, information on the response to antidiabetic drugs and other therapies 
(precision therapies). Future application of the findings of this approach should 
translate into benefits for the person with diabetes and for healthcare professional 
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The implementation of precision medicine in diabetes will also result in an 
improvement for our health system, since the proper use of resources must be based on 
relevant information (cost-effectiveness). 
We firmly believe that the new information resulting from studies such as ours, which 
combine innovative methodologies, will ultimately help physicians, health authorities 
and patients themselves, and help develop strategies to implement better management 
of the disease, using a more individualized targeted approach. 
 
17. FUNDING SOURCE 
 
Carlos III Health Institute Health Research Projects PI21/01163 
 
18. CONFLICT OF INTEREST 
The researchers have no conflict of interest 
 
LIST OF INDEPENDENT DOCUMENTS 
 
ANNEX 1. NOTEBOOK FOR COLLECTING DATA 
ANNEX 2. COORDINATING RESEARCHER COMMITMENT 
ANNEX 3. RESEARCHER COMMITMENT CENTER 
ANNEX 4. CEI CONFORMITY 
ANNEX 5. PATIENT INFORMATION SHEET 
ANNEX 6. INFORMED CONSENT FORM 
ANNEX 7. FINANCIAL REPORT 
ANNEX 8. CHARACTERISTICS OF CENTERS AND EXPECTED RESULTS 
ANNEX 9. PROMOTIONAL STUDY MATERIAL TO RECRUIT PATIENTS 
ANNEX 10. LIST OF CENTERS, PRINCIPAL INVESTIGATORS CENTERS 
 
 

 
 
 
 
 
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ANNEX 1. DATA COLLECTION NOTEBOOK  
Attached in a separate document. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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ANNEX 2. COMMITMENT OF THE PRINCIPAL INVESTIGATOR AND 
COORDINATOR 
The data of the researcher that appear in this document will be entered and processed 
in a file owned by the Research Institute Foundation of the Hospital de la Santa Creu i 
Sant Pau – IIB Sant Pau c/ Sant Antoni Maria Claret, 167, 08025 Barcelona, Tel: 93 
553 78 69, declared as a Data Management Center, and will be treated in accordance 
with the provisions of Organic Law 3/2018 Protection of Personal Data and digital 
rights guarantee. The researcher may exercise their rights of information, opposition, 
access, rectification or cancellation of the data recognized in said Law. 
Dr. Dídac Mauricio with DNI 46525502K from the Hospital de la Santa Creu i Sant 
Pau in Barcelona. 
It states: 
That has evaluated the study "Characterization of subgroups of type 2 diabetes at 
diagnosis: a necessary step towards precision medicine in diabetes, study: 
COPERNICAN" and whose promoter is the IIB Sant Pau Foundation. 
And you agree to: 
- Sign a commitment in which they recognize themselves as investigators of the study 
and affirm that they know the protocol and any modifications to it, and agree with it in 
all its terms. 
- Inform the research subjects and obtain their consent. 
- Collect, record and notify the data correctly, responding to its updating and quality 
before the appropriate audits. 
- Notify the sponsor of adverse events as established in the protocol. 
- Respect the confidentiality of the data of the participating subjects 
- Facilitate the monitoring visits of the monitor, the audits of the promoter and the 
inspections of the health authorities. 
- Know how to answer about the objectives, basic methodology and meaning of the 
results of the study before the scientific and professional community. 
- Sign the protocol and any modifications to it together with the promoter. 
- Contribute to disseminating the results of the study, in collaboration with the 
promoter. 
 
Investigator Signature: 
 
  
Date: 

 
 
 
 
 
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ANNEX 3. RESEARCHER COMMITMENT 
The data of the researcher that appears in this document will be entered and processed 
in a file owned by the foundationFoundation Institut de Recerca de l'Hospital de la 
Santa Creu i Sant Pau – IIB Sant Pau c/ Sant Antoni Maria Claret, 167, 08025 
Barcelona, Tel: 93 553 78 69, declared as Data Management Center, and will be 
treated in accordance with what is provided by Organic Law 3/2018 Protection of 
Personal Data and guarantee digital rights. The researcher may exercise their rights of 
information, opposition, access, rectification or cancellation of the data recognized in 
said Law. 
 
Dr. with DNI of the service of the center It states: 
That it has evaluated the study "Characterization of subgroups of type 2 diabetes at 
diagnosis: a necessary step towards precision medicine in diabetes, study: 
COPERNICAN" and whose promoter is the IIB Sant Pau Foundation. 
 
That he agrees to participate as principal investigator, and undertakes to: 
 
-Sign a commitment in which they recognize themselves as investigators of the study 
and affirm that they know the protocol and any modifications to it, and agree with it in 
all its terms. 
-Inform the research subjects and obtain their consent. 
-Collect, record and notify the data correctly, responding to its updating and quality 
before the appropriate audits. 
-Notify the promoter of adverse events as established in the protocol. 
-Respect the confidentiality of the data of the participating subjects 
-Facilitate the monitoring visits of the monitor, the audits of the promoter and the 
inspections of the health authorities. 
-Know how to answer about the objectives, basic methodology and meaning of the 
results of the study before the scientific and professional community. 
-I freely agree to participate in the study and give my consent for the access and use of 
my data under the conditions detailed in the study protocol. 
  
 
 
 
 
 
 
 
 
 
ANNEX 4.  
CEI CONFORMITY 
 
It will be included once the aforementioned agreement is obtained. 
Firma del Investigador:                            Fecha:   
 
 
 
Investigadores colaboradores: 
 
Nombre:   
DNI:    
 
Firma del Investigador: 
Fecha: 
 
 
Nombre:   
DNI:    
 
Firma del Investigador: 
Fecha: 
  

 
 
 
 
 
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ANNEX 5. PATIENT INFORMATION SHEET 
STUDY TITLE: Characterization of type 2 diabetes subgroups at diagnosis: a 
necessary step towards precision medicine in diabetes, study: COPERNICAN 
 
PROMOTER: IIB Sant Pau Foundation 
 
INTRODUCTION 
 
We are writing to inform you about a research study in which we invite you to 
participate. The study has received the approval of the Ethics Committee of the IIB 
Sant Pau Foundation and IDIAP Jordi Gol i Gurina , in accordance with current 
legislation. This study is funded by the IIB Sant Pau Foundation through the award of 
a FIS 2021 PI21/01163 project from the Carlos III Health Institute, which allocates its 
resources to the study of diabetes mellitus type 2. 
Our center participates in this study carried out in Catalonia. 
Our intention is that you receive the correct and sufficient information so that you can 
evaluate and judge whether or not you want to participate in it. To do this, read this 
information sheet carefully and we will clarify any doubts that may arise after reading 
it. In addition, you can consult with the people you consider appropriate. 
 
VOLUNTARY PARTICIPATION 
 
Your participation in this study is voluntary, and you may decide not to participate or 
change your decision and withdraw your consent at any time, without changing your 
relationship with your doctor or affecting your health care. 
 
THE PURPOSE OF THE STUDY 
 
To evaluate and characterize the relevant subgroups of type 2 diabetes at the time of 
diagnosis in our country. The results of this study could help us better understand the 
variety of type 2 diabetes, and identify different important subgroups that allow 
improving the management and treatment of the disease. 
 
STUDY OVERVIEW 
 
The study will be carried out in the primary care centers of the various health areas of 
Catalonia. This characterization consists of collecting a very complete series of 
clinical characteristics in all people, including those specifically characteristic of 
diabetes and also those of the person himself. This should allow us to contribute new 
knowledge in what is known as precision medicine, in this case applied to the 
precision diagnosis of diabetes. One of the problems we have in the management of 
type 2 diabetes is the variety of possible subgroups of patients that comprise it. We 
know, from previous research, that people with this type of diabetes do not have all the 
common characteristics at the beginning of the disease, nor do they evolve in the same 
way, nor do they respond in the same way to treatments, and they do not have the 
same risk of developing diabetes. complications. In addition, no treatment measures 

 
 
 
 
 
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are currently recommended for each person individually, and sharing decisions 
between the patient and health professionals. This makes it increasingly necessary that 
we obtain much more precise information on the different subgroups of people 
diagnosed with type 2 diabetes and individually characterize those that correspond to 
each specific patient profile. This information, which is what this project intends to 
generate, when diagnosing diabetes, should lead us to have much more precise 
information for decision-making by professionals, and shared with the affected person. 
The application of this strategy with more precise information in each case (precision 
medicine) should allow in the future that each person with type 2 diabetes receive 
individualized management of their condition, considering the specific factors of their 
case (precision medicine). personalized). 
 
Diagnosis of type 2 diabetes 
 
Type 2 diabetes used to appear in older ages, but the growing epidemic of overweight 
and obesity in the population of all ages is resulting in an increase in the number of 
people with type 2 diabetes also in the younger population. Obesity, which is in many 
cases linked to a sedentary lifestyle and an unhealthy diet, is one of the main causes 
that ultimately leads to the development of type 2 diabetes. 
 
The diagnosis of type 2 diabetes is usually late since the symptoms may go unnoticed 
or not be identified by the person as typical of diabetes, so it may even take several 
years without the person going to health centers to diagnose this condition. 
 
Visits and follow-up program 
 
Before participating in the study, you will be contacted by your family doctor or 
researcher at the center to explain the possibility of participating and explain all the 
study procedures. 
 
If your decision is to participate in the study, before scheduling your first visit, called 
an inclusion visit, you will be given a telephone questionnaire in order to detect 
possible symptoms or contacts of COVID-19 infection. If there is any suspicion, you 
will proceed according to local clinical practice recommendations, and your 
participation in the study will be postponed. 
 
If you agree to participate in the study, the local investigator at the center will review 
your medical records. Only one visit will be made for the study in which data related 
to alcohol or tobacco consumption, weight and height, waist circumference, blood 
pressure, information on other diseases suffered, medications taken, request for 
laboratory analysis will be collected. related to diabetes, possible complications you 
may have related to diabetes, and questionnaires about your diet and physical activity. 
 
Some primary care centers participating in this study have equipment to assess 
atherosclerosis. Atherosclerosis is a condition in which plaque made of fat, 
cholesterol, calcium, and other substances found in the blood builds up inside the 
arteries (blood vessel). In these centers you will be offered the possibility of 
performing a painless, safe and fast non-invasive diagnostic test (ultrasound) with a 

 
 
 
 
 
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short duration to evaluate the involvement of atherosclerosis in the blood vessels of 
the neck and legs. 
 
You will be scheduled for routine blood and urine tests, as recommended by current 
clinical practice guidelines. Laboratory procedures will be performed at local 
laboratories. Specific additional laboratory procedures for the determination of C-
peptide and antibodies that are considered non-routine parameters will also be 
performed at local laboratories from the same blood draw. These tests will help us 
better characterize your diabetes. 
 
Since current clinical practice includes assessment of chronic complications of 
diabetes (foot exam, eye disease screening program, problems with kidney function), 
other diseases and related clinical and laboratory variables of interest with diabetes, 
mortality, these data will be extracted by linking them with the database of electronic 
records of medical records (databases of Catalonia-SIDIAP/PADRIS, for specific 
causes of mortality through the INE) or through the electronic clinical record in the 
event that the link with the SIDIAP/PADRIS databases is not possible. Only if you 
have accepted monitoring of your disease with the Catalonia-SIDIAP/PADRIS 
databases, your encrypted CIP (Personal Identification Code) (transcribing your 
personal identification code with a key) will be sent to these databases. data to do data 
binding. 
 
Portability of data from other studies 
 
If you are participating or have participated in any other clinical research projects, you 
may transfer your data from these studies to this study. The data portability procedure 
from another study will be carried out by the research team with the permission 
granted by you in this informed consent. 
 
Withdrawal from the study 
 
Your participation in this study is completely voluntary, you can withdraw from the 
study at any time if you wish without having to explain to your doctor and without 
compromising in any way the treatment you have to receive. 
 
 
 
BENEFITS AND RISKS OF YOUR PARTICIPATION IN THE STUDY 
 
The study has no possibility of generating risk because it is an observational study 
without the specific use of medication, which is limited to an anonymous data record 
in a database that does not allow access to the patient's personal data. 
 
CONFIDENTIALITY 
 
The treatment, communication and transfer of personal data of all participating 
subjects will comply with the new legislation in the European Union (EU) on personal 
data, specifically Regulation (EU) 2016/679 of the European Parliament and of the 

 
 
 
 
 
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Council of April 27, 2016 on Data Protection (RGPD). Organic Law 3/2018, of 
December 5, on the Protection of Personal Data and guarantee of digital rights is also 
in force. In accordance with the provisions of the aforementioned legislation, you can 
exercise your rights of access, modification, opposition and cancellation of data, for 
which you must contact the study doctor. 
The data collected for the study will be identified by a code and only your study doctor 
and collaborators will be able to associate said data with you and with your medical 
history. Therefore, your identity will not be revealed to any person except for 
exceptions, such as in case of medical emergency or legal requirement. 
If the study is published or the results are disseminated in scientific publications or 
congresses, no data will be included that could provide information that helps to 
identify patients. 
Access to your personal information will be restricted to the study 
doctor/collaborators, health authorities (Spanish Agency for Medicines and Health 
Products), the Ethics Committee for Research with Medicines (CEI) and personnel 
authorized by the sponsor, when required to do so. verify the data and procedures of 
the study, but always maintaining their confidentiality in accordance with current 
legislation. 
 
It is also important that you know the following information related to your rights: 
 
In addition to the rights that you already know (access, modification, opposition and 
cancellation of data), you can currently also limit the processing of data that is 
incorrect, request a copy or transfer to a third party (portability) the data that you have 
provided for the study. To exercise your rights, you can contact your treating doctor 
and you must provide a document that proves your identity as the owner of the data 
(DNI), and indicate the right you wish to exercise. The promoter's data protection 
delegate will manage the request and will issue a response according to the case. The 
following steps will be carried out: your doctor will contact those responsible for 
managing the study using the data indicated in the study protocol, without disclosing 
in any case the personal data of the patient, but only indicating the code to which the 
holder corresponds, code of the study and code of the center, as well as the right that 
you have been asked to exercise. The doctor must not send the promoter the document 
proving the identity, since it was verified by him at the time of the request. 
We remind you that the data cannot be deleted, even if you stop participating in the 
study, to guarantee the validity of the research and to comply with legal duties and 
drug authorization requirements. You also have the right to contact the Spanish Data 
Protection Agency. C/ Jorge Juan, 6. 28001 Madrid ( https://www.aepd.es/es ) or the 
Catalan Dades Protection Authority ( https://apdcat.gencat.cat), if you are not satisfied. 
 
The center is responsible for the processing of your data and undertakes to comply 
with current data protection regulations. The data collected for the study will be 
identified by a code, so that information that can identify you is not included, and only 
your study doctor / collaborators will be able to relate said data to you and your 
medical history. Therefore, your identity will not be disclosed to any other person 
except the health authorities, when required or in cases of medical emergency. The 
Research Ethics Committees, the representatives of the Health Authority in matters of 
inspection and the personnel authorized by the Promoter, may only access to check the 

 
 
 
 
 
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personal data, the clinical study procedures and compliance with the standards of good 
clinical practice. (always maintaining the confidentiality of the information).  
 
Responsible for data processing: Institute Catalan of Health 
 
Responsible for data processing: SIDIAP/PADRIS 
 
Legal basis of the treatment: RGPD: 6.1 a) the interested party gave their consent for 
the treatment of their personal data for one or several specific purposes. 
 
The Researcher and the Promoter are obliged to keep the data collected for the study 
for at least 5 years after its completion. Subsequently, your personal information will 
only be kept by the health care center and by the sponsor for other scientific research 
purposes if you have given your consent to do so, and if permitted by applicable law 
and ethical requirements. 
 
If we transfer your encrypted data within the EU to our group entities, service 
providers or scientific researchers who collaborate with us, the participant's data will 
be protected with safeguards such as contracts or other mechanisms by data protection 
authorities. data. If you want to know more about it, you can contact the Data 
Protection Officer of the institution or the promoter Institut de Recerca de l'Hospital de 
la Santa Creu i Sant Pau – IIB Sant Pau c/ Sant Antoni Maria Claret , 167, 08025 
Barcelona, Tel: 93 553 78 69, email dpo_ir@santpau.cat, or with the Spanish Data 
Protection Agency at Jorge Juan, 6, 28001 Madrid (https: // www .aepd.es / es ) or the 
Catalan Dades Protection Authority ( https://apdcat.gencat.cat ) 
Biological samples 
 
Collection and use 
Your participation in this study entails obtaining and using biological samples for 
research purposes, for which Law 14/2007 on biomedical research and Royal Decree 
1716/2011 will be observed, regulations that guarantee respect for your rights . . By 
signing this document, reviewed and favorably evaluated by the Research Ethics 
Committee that has approved this clinical study, you agree to the use of your samples 
for the purposes of this study. 
 
What is a biobank?: Institution to promote research and health 
 
Biobanks are authorized establishments that house an organized set of biological 
samples and associated information under the conditions and guarantees of quality and 
safety required by current legislation. Said samples and their associated information 
are available to those national or international research centers or institutions that 
officially request them from the Biobank. The samples and data may therefore be 
transferred to European countries or from other parts of the world, always for projects 
that have been approved by the External Committees and by the Scientific Director of 
the Biobank. 
 
From the donated samples, in the cases in which the research requires it, genetic 
studies will be carried out that on occasions could refer to the complete sequencing of 

 
 
 
 
 
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your genome, and from them information about your health and that of your loved 
ones can be obtained. relatives. Action will always be taken to ensure the protection of 
this information (see section on data protection and confidentiality). 
 
Biological samples will be kept indefinitely in the Biobank or until they are consumed 
in research projects. In the event of a possible closure of the Biobank, the samples and 
associated data would be transferred to another authorized Biobank. The information 
on the destination of the samples will be available to you in the National Registry of 
Biobanks for Biomedical Research of the Carlos III Health Institute. If an additional 
sample is necessary, we request your permission for the health institution to contact 
you to request your collaboration again. 
 
The samples will always be transferred anonymously, without associated personal 
information. 
 
Discomfort and possible risks 
 
No major risk to participants 
The only discomfort may derive from the blood draw. Sampling can cause a burning 
sensation at the point where the needle is inserted into the skin and cause a small 
bruise or a mild infection that disappears in a few days. More rarely, dizziness may 
appear at the time of blood collection. 
 
During the routine blood and urine clinical visit, part of the blood/urine samples will 
be stored for later analysis. These samples will be used to determine the advanced 
lipoprotein profile (analysis of fats in the blood, such as cholesterol and triglycerides), 
which will allow the detection of some specific parameters as part of the objectives of 
the study. Your samples will also be used to determine metabolites (substance 
produced during digestion or other body chemical processes) and genes (information 
that determines our traits) related to diabetes. 
 
Apart from this purpose of biological samples, it is also possible that your samples 
will be used for other studies related to diabetes, non-diabetes related, or genetic 
studies only and when you accept one of these options in the informed consent form. 
for donation and preservation of biological samples. In the event that you accept these 
purposes of use of your samples, you will be informed by your doctor regarding the 
results obtained if you wish. 
The samples obtained will be labeled with a code to maintain confidentiality, will be 
processed in local laboratories, and later stored by the Biobank of the Research 
Institute of the Hospital de la Santa Creu i Sant Pau. 
 
Responsible for data processing 
The personal data collected will be obtained, processed and stored in a file under the 
responsibility of the Hospital de la Santa Cruz y San Pablo Research Institute 
Foundation for research purposes. The file wants to guarantee the quality, security and 
traceability of the data and biological samples stored as well as of the associated 
procedures, in the terms established in Law 14/2007, of July 3, on Biomedical 

 
 
 
 
 
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Research; complying at all times with the duty of secrecy, in accordance with current 
legislation on the protection of personal data. 
 
The identification of the biological samples will be subjected to a coding process. 
Each sample is assigned an identification code that is detached from personal data. 
Only authorized personnel may associate their identity with the aforementioned codes. 
Through this process, the researchers who request samples will not be able to know 
any information that reveals their identity. Likewise, although the results obtained 
from the research carried out with your samples are published in scientific journals, 
your identity, or that of your family in the event that they participate jointly, will not 
be disclosed. 
In those studies in which no potentially useful results for your health are expected, and 
in accordance with the corresponding Ethics Committee, the samples and data may be 
anonymized, that is, there will be no possibility of re-associating the sample with your 
identity. . 
You may exercise your rights of access, rectification, cancellation and objection, as 
well as obtain information on the use of your samples and associated data, by 
contacting the legal person responsible for the study 
 
Biobank. Sant Pau Biomedical Research Institute 
Santa Cruz and San Pablo Hospital Research Institute Foundation (hereinafter, 
FIRHSCSP or Foundation). Registered office: Calle San Antonio María Claret , 167, 
08025 Barcelona. Registered in the Registry of Foundations of the Government of 
Catalonia, with number 708. CIF: G-60136934. Telephone: 93.553.76.13. Contact 
email: biobanc@santpau.cat . 
Promoter: The principal investigator (Dr. Dídac Mauricio DNI: 46525502K) of the 
study and the Promoter- Research Institute of the Hospital de la Santa Creu i Sant Pau 
– IIB Sant Pau, c/ Sant Antoni Maria Claret , 167 08025 Barcelona, Tel: 93 553 78 69. 
Contact email: dmauricio@santpau.cat  
 
Purposes 
Your data will be processed solely to carry out research to advance knowledge of 
diabetes. 
 
Legal basis of the treatment 
RGPD: 6.1 a) the interested party gave their consent to the processing of their personal 
data for one or more specific purposes. 
 
Rights of interested persons 
Interested parties may exercise, if they wish, the rights of access, rectification and 
deletion of data, as well as request that the processing of their personal data be limited, 
oppose the processing, and request the portability of their data, through the following 
media: 
- By sending a written request to the indicated postal address. 
- By sending a request to the email: dpo_ir@santpau.cat 
 

 
 
 
 
 
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The interested parties may, in relation to those treatments that are based on obtaining 
their consent, withdraw their consent through the procedure detailed in the previous 
paragraph. 
 
Also, if you believe that the protection of any of your rights has been violated, you can 
file a claim with the Spanish Agency for Data Protection (www.aepd.es). 
 
GRATITUDE 
Thank you very much for reading this study information document. If you decide to be 
part of the study, you will need to sign the informed consent form. A copy of this 
information document and the consent document will be given to you for your 
retention. 
We think that it is a necessary study, which will help us to better understand this 
pathology and thus be able to improve patient care. 
Your participation is important and we greatly appreciate your collaboration. We 
remain at your disposal for any clarification or question you may have. 
 
CONTACT IN CASE OF DOUBTS 
If you need any information or for any other reason, do not hesitate to contact the 
study doctor, Dr._______________________, at the primary care 
center________________________________, Address :_ 
____________________________, contact telephone number: _____________ 
 
 

 
 
 
 
 
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ANNEX 6. INFORMED CONSENT FORM 
STUDY TITLE: Characterization of type 2 diabetes subgroups at diagnosis: a necessary 
step towards precision medicine in diabetes, studio: COPERNICAN 
PROMOTER: IIB Sant Pau Foundation 
 
I (name and surnames -written in handwriting by the participating subject-) 
 
........................................................... ........................................................... 
..................... 
- I have read the information sheet that has been given to me 
- I was able to ask questions about the study. 
- I have received enough information about the study. 
- I have spoken with: 
........................................................... .......................................... 
(Name and surname of the researcher) 
I understand that my participation is voluntary. 
I understand that I can withdraw from the study: 
- Whenever you want 
- Without having to explain. 
- Without this affecting my medical care. 
 
 
 
I accept all the options mentioned below 
YES 
NO 
 
 
I accept that my electronic medical record data is crossed with 
clinical databases to track my disease 
 
 
I accept that the follow-up of my disease is done through the 
electronic medical record 
 
 
I agree to be contacted for future studies related to diabetes 
I accept the transfer of my data under the conditions detailed in 
the information sheet 
 
 
I accept portability of my data from other research studies 
 
I freely give my consent to participate in the study, and I give my consent for the 
access and use of my data under the conditions detailed in the information sheet. 
Patient  
 
 
 
 
Signature: Investigator Signature: 
Name:  
 
 
 
 
Name: 
 
Date: ____/____/____  
 
 
 
Date: ____/____/____ 
 
(Name and date, handwritten by the participating subject) 
This document will be signed in duplicate, one copy being kept by the researcher 
and another by the patient. 
 
 

 
 
 
 
 
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INFORMED CONSENT FORM FOR WITNESS 
 
 
STUDY TITLE: Characterization of type 2 diabetes subgroups at diagnosis: a necessary 
step towards precision medicine in diabetes, study: COPERNICAN 
 
PROMOTER: IIB Sant Pau Foundation, 
 
I…………………………………………. (name and surname of the witness) declare 
under my responsibility that ……………………………….……. (Name and surname 
of the participant) I have read (or it has been read to him, in the event that the patient 
cannot read), the information sheet that has been given to him. 
  
- 
You have been able to ask questions about the study. 
- 
You have received enough information about the study. 
- 
Have you talked to: 
........................................................... .......................................... 
(Name and surname of the researcher) 
 
- 
You understand that your participation is voluntary. 
- 
You understand that you can withdraw from the study: 
• Whenever you want 
• Without having to explain. 
• Without this affecting my medical care. 
 
You will receive a signed and dated copy of this informed consent document 
You freely agree to participate in the study and give your consent for the access and 
use of your data under the conditions detailed in the information sheet. 
 
Witness  
 
 
 
 
Signature: Investigator Signature: 
 
Name:  
 
 
 
 
Name: 
 
 
Date: ____/____/____  
 
 
 
Date: ____/____/____ 
 
(Name and date, handwritten by the witness) 
 
 
 
 
 
 
This document will be signed in duplicate, keeping one copy for the investigator 
and another for the witness. 
 
 
 

 
 
 
 
 
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INFORMED CONSENT FORM FOR DONATION AND CONSERVATION OF 
BIOLOGICAL SAMPLES FOR THE BIOBANK 
STUDY TITLE: CHARACTERIZATION OF SUBGROUPS OF TYPE 2 DIABETES 
AT DIAGNOSIS: A NECESSARY STEP TOWARDS PRECISION MEDICINE IN 
DIABETES, COPERNICAN STUDY 
PROMOTER: IIB Sant Pau Foundation 
 
• I understand why the promoter is preserving the biological samples for the biobank. 
• I have had the opportunity to ask questions. All my questions have been answered. 
• I understand that I will be given a copy of this consent form after I sign it. 
• I understand and authorize the processing of my personal data as indicated in the Patient 
Information Sheet 
1. I agree that my biobanked blood and urine samples may be used for: 
 
 
I accept all the options mentioned below 
YES 
NO 
 
 
 
Research related to the study 
 
 
 
Future research related to diabetes 
 
 
 
Future research not related to diabetes 
 
 
 
Future genetic studies 
 
 
I want to know the results of the tests carried out with my biological 
samples 
 
 
 
As for the full study, your participation in the biobanking portion of the study sample donation 
is voluntary and you are free to withdraw your consent at any time for any reason without 
influencing your participation in the main study. 
………………………………… ……………………………………………………. 
Patient name Patient signature            Date  
 
………………………………… ……………………………………………………. 
Name of the investigator/ delegate Signature of the investigator/ delegate Date 

 
 
 
 
 
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REVOCATION OF CONSENT form for participation in the study Characterization of 
subgroups of type 2 diabetes at diagnosis: a necessary step towards precision medicine in 
diabetes, study: COPERNICAN 
 
I wish to withdraw from the study Characterization of subgroups of type 2 diabetes at diagnosis: a 
necessary step towards precision medicine in diabetes 
However, I allow: 
• 
Follow-up of the study as described in the protocol 
If not 
 
…………………………………....……………………………………………………. 
Name of patient 
…………………………………..   
……………………………………………………. 
Place and Date    
 
 
 
Signature of the patient 
 
 
…………………………………....……………………………………………………. 
Name of the investigator/delegate 
 
…………………………………..   
 
……………………………………………………. 
Place and Date    
 
 
 
Signature of the researcher/delegate 
 
 

 
 
 
 
 
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REVOCATION OF CONSENT Form FOR DONATION AND CONSERVATION OF 
BIOLOGICAL SAMPLES FOR BIOBANK in the study Characterization of type 2 
diabetes subgroups at diagnosis: a necessary step towards precision medicine in diabetes, 
COPERNICAN study 
 
PER DONOR: 
/ Mrs. ........................................................... .......................................... with DNI ...... ....................... I 
cancel the consent given on the date ............. of ....... .............. of 20 ...... and I do not wish to continue 
voluntary donation in the study Characterization of subgroups of type 2 diabetes at diagnosis: a necessary 
step towards precision medicine in diabetes, which I am ending with today's date. 
 I REQUEST THE DELETION OF THE SAMPLE ONLY 
 I REQUEST THE DELETION ONLY OF MY PERSONAL DATA 
The sample will be irreversibly anonymized and may be used in research projects. 
 I REQUEST THE TOTAL DELETION OF MY DATA AND SAMPLES 
signed : 
…………………………………....……………………………………………………. 
Name of patient 
…………………………………..   
……………………………………………………. 
Place and Date    
 
 
 
Signature of the patient 
 
 
…………………………………....……………………………………………………. 
Name of the investigator/delegate 
 
…………………………………..   
 
……………………………………………………. 
Place and Date    
 
 
 
Signature of the researcher/delegate 
 
 

 
 
 
 
 
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ANNEX 7. FINANCIAL REPORT 
Study title: “Characterization of type 2 diabetes subgroups at diagnosis: a necessary step 
towards precision medicine in diabetes.” 
 
Protocol code: COPERNICAN 
 
This study is independent of the Pharmaceutical Industry, which is why the exemption 
from fees is requested from the Clinical Research Ethics Committees. 
 
The study is funded by a grant from the Health Research Fund (FIS). This aid will go 
to: 
 
• Researcher meetings 
• Preparation of the electronic CRD 
• monitoring 
• Data extraction 
• Data management and analysis 
• Biobanks 
• GADA65, IA-2 and C-peptide determinations 
 
No payment will be made to the investigators for participating in this trial or to 
participating patients. 
 
To clarify that in order to carry out this study, tests other than those used in the 
treatment of this disease in primary care in routine clinical practice are not required. The 
IIB Sant Pau Foundation assumes the financing of the study in accordance with the 
guidelines of this protocol, which in any case will be independent of the results 
obtained. 
 
 
 
Center Investigator Signature:   
 
Date: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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ANNEX 8. Center characteristics and expected results  
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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ANNEX 9. Study promotional material to recruit patients 
 
Do you have newly 
diagnosed type 2 diabetes? 
 
In our center, the clinical field study is being 
carried out: Characterization of subgroups of 
type 2 diabetes at diagnosis: a necessary step 
towards precision medicine in diabetes. 
 
If you have been diagnosed with type 2 
diabetes in the last 3 months, you may be a 
candidate for this prospective study that is 
being carried out in Catalonia. 
 
With your participation, you can help us 
better characterize your disease, learn more 
about its evolution and complications, in 
order to apply more personalized treatments 
to each patient. 
 
 
Procedures: 
 
A single study visits with your GP 
A blood and urine test 
 
If you are interested in participating and 
would like to receive more information, 
contact us by email: 
 
XXX@XXXX.COM 
 
 
 
 
Contact information participating centers: 
 
XXX 
 
 
 

 
 
 
 
 
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ANNEX 10. List of centers, principal investigators centers  
 
 
Center 
Principal Investigator Center 
Hospital de la Santa Creu i Sant Pau-
Barcelona 
Dr. Didac Mauricio 
Consortium Centers Integral 
Sanitation 
 
CAP Sagrada Familia- Barcelona 
Dra. Natalia Riera 
Centers Institute Catalan Health  
 
Vilanova University Hospital - Lleida 
Dra. Marta Hernandez 
CAP Tàrrega 
Dra. Neus Miró 
CAP Balaguer 
Dr. Jesús Pujol 
CAP September 11th _ 
Dr. Monica Solanes 
CAP Bordeta 
Dr. Antonieta Lafarga 
CAP Balafia-Pardinyes 
Dra. Sandra Guerrero 
CAP Alcarràs 
Dra. Mireia Marin 
CAP Agramunt 
Dra. Meritxell Torres 
CAP Eixample (Lleida) 
Dra. Laia Llubes  
CAP La Mina 
Dr. Manel Mata 
CAP Besòs 
Dra. Elena Hernandez Boluda 
CAP Sant Martí 
Dr. Francesc Xavier Cos Claramunt 
CAP Sarrià 
Dr. Gabriel Cuatrecasas 
CAP Casc Antic  
Dr. Cristian Llacer 
CAP El Clot 
Dra. Anna Massana Raurich 
CAP Poblenou 
Maria Isabel Prieto Fernandez 
CAP: Primary Care Center;