RESEARCH ARTICLE
Early prevention of diabetes microvascular
complications in people with hyperglycaemia
in Europe. ePREDICE randomized trial. Study
protocol, recruitment and selected baseline
data
Rafael GabrielID1,2☯*, Nisa Boukichou AbdelkaderID3,4☯, Tania AcostaID3,5☯,
Aleksandra Gilis-Januszewska6‡, Ricardo Go´mez-Huelgas7‡, Konstantinos Makrilakis8‡,
Zdravko Kamenov9‡, Bernhard Paulweber10‡, Ilhan Satman11‡, Predrag Djordjevic12‡,
Abdullah AlkandariID13‡, Asimina Mitrakou14‡, Nebojsa Lalic15‡, Stephen Colagiuri16‡,
Jaana Lindstro¨m17‡, Jesu´s Egido18‡, Andrea Natali19‡, J. Carlos Pastor20‡,
Yvonne Teuschl21‡, Marcus Lind22‡, Luis Silva3‡, Ruy Lo´pez-Ridaura23‡,
Jaakko Tuomilehto1,2,17,24,25☯, On behalf of the e-PREDICE Consortium¶
1 Departamento de Salud Internacional, Escuela Nacional de Sanidad, Instituto de Salud Carlos III, Madrid,
Spain, 2 World Community for Prevention of Diabetes Foundation (WCPD), Madrid, Spain, 3 EVIDEM
CONSULTORES, Madrid, Spain, 4 Asociacio´n para la Investigacio´n y Prevencio´n de la Diabetes y
Enfermedades Cardiovasculares (PREDICOR), Madrid, Spain, 5 Department of Public Health. Universidad
del Norte, Barranquilla, Colombia, 6 Uniwersytet Jagiellonski, Collegium Medicum, Krakow, Poland,
7 Fundacio´n FIMABIS. Servicio Andaluz de Salud (SAS), Malaga, Spain, 8 National and Kapodistrian
University of Athens, Athens, Greece, 9 University Multi-Profile Hospital for Active Treatment Alexandrovska
EAD, Sofia, Bulgaria, 10 Gemeinnuetzige Salzburger Landeskliniken Betriebsgesellschaft, (SALK) Salzburg,
Austria, 11 Istanbul University, Istanbul, Turkey, 12 General Hospital Medical System Beograd—MSB
Belgrade Serbia, Beograd, Serbia, 13 Dasman Diabetes Research Institute, Kuwait, Kuwait, 14 Alexandra
Hospital, University of Athens, Athens, Greece, 15 Faculty of Medicine, University of Belgrade, Belgrade,
Serbia, 16 The University of Sydney, Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders,
Sydney, Australia, 17 National Institute for Health and Welfare, Helsinki, Finland, 18 Renal, Vascular and
Diabetes Research Laboratory, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic
Disorders (CIBERDEM), Instituto de Investigacio´n Sanitaria Fundacio´n Jime´nez Dı´az, Universidad
Auto´noma, Madrid, Spain, 19 Department of Internal Medicine, Universita di Pisa, Pisa, Italy, 20 Instituto
Universitario de Oftalmobiologı´a Aplicada(IOBA), Universidad de Valladolid, Hospital Clı´nico Universitario,
Valladolid, Spain, 21 Department for Clinical Neurosciences and Preventive Medicine, Danube University
Krems, Krems, Austria, 22 Va¨stra Go¨talands La¨ns Landsting, Gothenburg, Sweden, 23 Instituto Nacional de
Salud Pu´bica, Cuernavaca, Me´xico, 24 University of Helsinki, Helsinki, Finland, 25 King Abdulaziz
University, Jeddah, Saudi Arabia
☯ These authors contributed equally to this work.
‡ These authors also contributed equally to this work.
¶ Membership of the e-PREDICE Study Consortium is provided in the Acknowledgments.
* rgabriel@ceiis.org
Abstract
Objectives
To assess the effects of early management of hyperglycaemia with antidiabetic drugs plus
lifestyle intervention compared with lifestyle alone, on microvascular function in adults with
pre-diabetes.
PLOS ONE
PLOS ONE | https://doi.org/10.1371/journal.pone.0231196 April 13, 2020 1 / 23
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OPEN ACCESS
Citation: Gabriel R, Boukichou Abdelkader N,
Acosta T, Gilis-Januszewska A, Go´mez-Huelgas R,
Makrilakis K, et al. (2020) Early prevention of
diabetes microvascular complications in people
with hyperglycaemia in Europe. ePREDICE
randomized trial. Study protocol, recruitment and
selected baseline data. PLoS ONE 15(4):
e0231196. https://doi.org/10.1371/journal.
pone.0231196
Editor: Shahrad Taheri, Weill Cornell Medical
College in Qatar, QATAR
Received: May 9, 2019
Accepted: March 14, 2020
Published: April 13, 2020
Copyright: © 2020 Gabriel et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: The clinical trial is
currently ongoing, patients and data are being
managed in a masked fashion. Data cannot be
made publicly available since data would
compromise confidentialty and might reveal
identity or location of participants. Additionaly,
public availability of data would be in violation of
the Spanish Organic Law 15/1999 of protection of
personal data (consolidated text 5/3/2011) and the
Methods
Trial design: International, multicenter, randomised, partially double-blind, placebo-con-
trolled, clinical trial.
Participants
Males and females aged 45–74 years with IFG, IGT or IFG+IGT, recruited from primary
care centres in Australia, Austria, Bulgaria, Greece, Kuwait, Poland, Serbia, Spain and
Turkey.
Intervention
Participants were randomized to placebo; metformin 1.700 mg/day; linagliptin 5 mg/day or
fixed-dose combination of linagliptin/metformin. All patients were enrolled in a lifestyle inter-
vention program (diet and physical activity). Drug intervention will last 2 years. Primary Out-
come: composite end-point of diabetic retinopathy estimated by the Early Treatment
Diabetic Retinopathy Study Score, urinary albumin to creatinine ratio, and skin conductance
in feet estimated by the sudomotor index. Secondary outcomes in a subsample include insu-
lin sensitivity, beta-cell function, biomarkers of inflammation and fatty liver disease, quality
of life, cognitive function, depressive symptoms and endothelial function.
Results
One thousand three hundred ninety one individuals with hyperglycaemia were assessed for
eligibility, 424 excluded after screening, 967 allocated to placebo, metformin, linagliptin or to
fixed-dose combination of metformin + linagliptin. A total of 809 people (91.1%) accepted
and initiated the assigned treatment. Study sample after randomization was well balanced
among the four groups. No statistical differences for the main risk factors analysed were
observed between those accepting or rejecting treatment initiation. At baseline prevalence
of diabetic retinopathy was 4.2%, severe neuropathy 5.3% and nephropathy 5.7%.
Conclusions
ePREDICE is the first -randomized clinical trial with the aim to assess effects of different
interventions (lifestyle and pharmacological) on microvascular function in people with pre-
diabetes. The trial will provide novel data on lifestyle modification combined with glucose
lowering drugs for the prevention of early microvascular complications and diabetes.
Registration
- ClinicalTrials.Gov Identifier: NCT03222765
- EUDRACT Registry Number: 2013-000418-39
Introduction
The World Health Organization (WHO) defines ‘Intermediate hyperglycaemia’ (pre-diabetes)
as 2 h post 75 g oral glucose tolerance test (OGTT) plasma glucose (2h PG) levels of 7.8–11.0
mmol/l (Impaired Glucose Tolerance–IGT-) or fasting plasma glucose (FPG) of 6.1–6.9
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PLOS ONE | https://doi.org/10.1371/journal.pone.0231196 April 13, 2020 2 / 23
European Law (EU) 2016/679 from European
Parlament and European Council of 27 of April
2016 about Data Protection (RGPD). The data
Access Committee of Consejerı´a de Sanidad de la
Comunidad de Madrid” address: c/Plaza Carlos
Trı´as Bertra´n n˚7 (Edif. Sollube) Madrid 28020;
(protecciondedatos.sanidad@madrid.org) could
consider those request that do not involve any
conflict with these legal regulations. Any acceptable
request will be processed and alsoevaluated by the
ePREDICE Steering Committee.
Funding: All the funding or sources of support
received during this specific study: - European
Commission, FP7 EC-GA No. 279074 - Merck-
Serono, Germany - Boeringher Ingelheim,
Germany (IIS Program. Grant number 1218.166) -
Instituto de Salud Carlos III, Spain PI11/01653 The
funders had no role in study design, data collection
and analysis, decision to publish, or preparation of
the manuscript.
Competing interests: the authors received funding
from Merck Serono GmbH and Boehringer
Ingelheim. This does not alter our adherence to all
the PLOS ONE policies on sharing data and
materials.
mmol/l with 2 h PG <7.8 mmol/l (Impaired Fasting Glucose–IFG-) [1]. Progression towards
manifest diabetes type 2 (T2D) approximate ranges between 5 and 10% per year: 4–6% for iso-
lated IGT; and 6–9% for IFG plus IGT [2–4].
People with pre-diabetes have a significantly increased risk for microvascular disease:
nephropathy, neuropathy, retinopathy, as well as macrovascular disease and mortality [5–11].
In addition, it has been shown that people with pre-diabetes have generalized microvascular
dysfunction and sequelae representing end-organ damage typical of diabetes [12]. Based on
such evidence it can be proposed that the definition of pre-diabetes should not only be cen-
tered on glucose abnormalities, but should incorporate also the microvascular involvement
among its criteria [13, 14].
A recent meta-analysis of published clinical trials on the prevention of T2D have showed
the benefits of lifestyle intervention in delaying the onset of T2D in patients with pre-diabetes
[15]. In addition, several antidiabetic drugs such as acarbose, metformin, rosiglitazone, piogli-
tazone and liraglutide have shown benefit for prevention of diabetes in pre-diabetic individuals
[16–20]. However, the evidence for the prevention of microvascular complications in people
with pre-diabetes is scarce. Few prevention trials have evaluated the potential benefits of life-
style or drug treatment on microvascular complications in pre-diabetes. Clinical evidence
regarding the microvascular benefit of lifestyle or metformin in prediabetes was inconclusive
in the DPP [21]. Recently, the Carmelina study has shown preliminary evidence on the benefits
of linagliptin for prevention of microvascular impairment in type 2 diabetes [22]. To our
knowledge thus far no trial has explored the extent to which microvascular function can be
preserved, and hence complications prevented, when combining lifestyle interventions with
early pharmacological treatment in people with pre-diabetes.
The specific aim of the ePREDICE trial is to assess the effects of early intensive management of
hyperglycaemia with linagliptin, metformin or their combination, added to lifestyle intervention,
compared with lifestyle intervention alone, on microvascular impairment (retinal, renal and
peripheral nerves) in adults with pre-diabetes. This paper describes the study design, enrolment,
and basic demographic, epidemiological and clinical characteristics of participants at baseline.
Material and methods
Study design
ePREDICE is a multicenter, International, independent, randomized, double-blind, placebo-
controlled, clinical trial. Participants are randomised with equal probability to four parallel
study arms: placebo, metformin, linagliptin, and fixed-dose combination of linagliptin/metfor-
min. Lifestyle intervention (diet and physical activity) is delivered to all patients. The active
intervention will last for 2 years and patients will be followed-up during an additional observa-
tional period of one year.
Study population
Inclusion criteria. People with pre-diabetes selected from several clinical centers in Aus-
tralia, Austria, Bulgaria, Greece, Kuwait, Poland, Serbia, Spain and Turkey.
Men and women aged 45–74 years with IFG: FPG 6.1 to 6.9mmol/l and OGTT 2h PG:
<7.8mmol/L; or IGT: FPG <7.0mmol/L and OGTT 2h PG>_7.8 and<11.1mmol/L) or both
conditions together.
Exclusion criteria. Type 1 diabetes; known or screen-detected T2D; use of any antidiabetic
drug within the 3 months prior to inclusion, any previous cardiovascular event, stroke or
revascularization procedure of any arterial territory; morbid obesity (Body Max Index>45);
current renal replacement therapy; renal function impairment: estimated glomerular filtration
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rate (eGFR<60 ml/min/1.73m2); diagnosis of liver cirrhosis or chronic hepatitis; previous
diagnosis of acute or chronic pancreatitis; elevation of pancreatic enzymes (amylase/Lipase)
>3 times of the upper normal ranges; diagnosis of chronic heart failure (NYHA class III or
higher); organ transplantation or waiting for organ transplantation; diagnosis of malignant
neoplasm requiring chemotherapy, surgery, radiation or palliative therapy or end-stage or
metastatic cancer; known hypersensitivity to trial products or related products; known use of
non-prescribed narcotics or illicit drugs; simultaneous participation in any other clinical trial
of an investigational agent; females of childbearing potential who are pregnant, breast-feeding
or intend to become pregnant; dementia, mental disorder or evident cognitive impairment;
unable to give written informed consent; chronic institutionalization (nursing/mental health
home, hospital, prison) conditions impeding retinal assessment as cataract, ocular surgery in
the previous month, concomitant intraocular treatment (retina or choroid), tropicamide
allergy; complete amputation of one/ both hands or one/both feet and any other circumstance
that in the investigator opinion could interfere with the trial initiation, visit schedules or
procedures.
Primary endpoint
Two-year change in the microvascular Index, defined as a linear combination of three vari-
ables: the retinal “Early Treatment of Diabetic Retinopathy Study (ETDRS) score, the urinary
albumin to creatinine ratio (UACR) and the sudomotor index using the SUDOSCAN1
device.
Secondary endpoints
Incidence of diabetes; quality of life, cognitive function, depressive symptoms, fatty liver index,
insulin sensitivity, beta-cell function, and biomarkers of inflammation and endothelial dys-
function in a subsample of participants.
Safety endpoints
Incidence of serious adverse events (SAE) and incidence of adverse events of special interest
related to specific drug treatment as hypoglycaemic episodes, neoplasms and pancreatitis.
Intervention groups
Placebo (matched to linagliptin) twice a day plus lifestyle modification; metformin 1700 mg/
day plus lifestyle modification; linagliptin 5 mg/day plus lifestyle modification; and fixed-dose
combination of linagliptin 5 mg/day and metformin 1,700 mg/day plus lifestyle modification.
Lifestyle intervention
All randomized patients, regardless of drug treatment, receive similar lifestyle intervention
program, aimed at promoting several lifestyle habits simultaneously. The lifestyle intervention
program contains informative as well as behavioural and motivational modules and consists of
two individual -sessions and 12 group sessions (up to 15 participants per session). The pro-
gram follows the process model for supporting lifestyle behaviour changes proposed by the
EU-funded IMAGE project (http://www.image-project.eu/). Group-sessions are repeated
every month during the first six months of the trial, and thereafter every three months. Indi-
vidual sessions last for one hour and group sessions 1, 5 hours. The lifestyle goals are based on
those of the Finnish Diabetes Prevention Study translated into food intake [23]. The informa-
tive modules of nutrition and physical activity encourage participants to increase consumption
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of vegetables, fruits and berries, legumes, whole-grain cereal, vegetable sources of fat and pro-
tein (nuts, legumes), olive or rapeseed oil, and fish over unhealthy food choices such as fast
food, refined grains and sweet treats. The dietary intervention has been culturally adjusted to
local conditions and food supply while retaining the same goals. Optionally, based on local
centre resources, physical activity intervention was delivered by group coaching (two sessions
per week starting at month-3), and facilitate access to local gyms and sport clubs; otherwise
physical activity is strongly emphasized during the group sessions. The intervention is deliv-
ered by staff nurses or nutritionists or “coachers” previously trained by experts.
Sample size
Since there is no published data on the efficacy of pharmacological treatment compared with
lifestyle intervention to reduce microvascular dysfunction in pre-diabetes, the sample size esti-
mation was challenging. We used feet skin conductance sudomotor index (ESC), a proxy of
early peripheral neuropathy measured with the SUDOSCAN device to detect changes in small
fibres of peripheral nerves earlier than the occurrence of clinical neuropathy, which takes a
long time to develop [24].
SUDOSCAN calculates feet ESC automatically, without the influence of observer bias. The
cardiovascular autonomic neuropathy risk score is derived from feet ESC values adjusted for
age and Body Max Index. For sample size and power calculation we used 1-year changes in
SUDOSCAN parameters collected in a previous pilot intervention study in pre-diabetic
patients (data not published).Sample size and power calculations were performed with the vali-
dated public statistical software GRANMO, version 7.0 (https://www.imim.cat/
ofertadeserveis/software-public/granmo/).
Based on a pilot study, we considered the most unfavourable outcome result as an absolute
difference between drug and lifestyle intervention of 1.8 units in ESC, a common standard
deviation of 12.1 in the whole population, follow-up dropout rate of 25%, correlation between
two SUDOSCAN measurements 0.80, size ratio lifestyle alone group /drug group 1:3, two-
sided test alpha risk 0.05, and beta risk 0.20. Using all these assumptions, the total calculated
sample size is 896 individuals (224 individuals per arm). The statistical power of this sample to
detect significant difference between lifestyle intervention alone and the three drug arms
together for SUDOSCAN-ESC is 82%.
Randomization procedure
Randomization was centralized and stratified by center with permuted block within each cen-
tre to ensure balance between treatment overtime and within centres. People were equally allo-
cated to any of the four 4 different groups (p = 0.25). The design of the study was partially
double-blinded, only between one of the active drug arms (linagliptin only) and the placebo
arm, and single-blinded (only for the patient) for the arm with metformin alone and the fixed
combination of metformin/linagliptin. Given the partially blinded design, we randomly varied
block sizes to avoid predictability of treatment assignment and selection bias. A specific web-
based, central, independent, randomization tool under OpenClinica1 software was used for
randomization. Random blocks were allocated to each centre as needed (dynamic allocation of
blocks). The coordinating centre (EVIDEM) centrally generated the random allocation
sequence and assigned participants to each intervention. Each clinical centre enrolled partici-
pants centrally assigned to each treatment group.
Several possible situations were foreseen in advance for randomization code breaking
(unmasking): a) end of experimental treatment at month 24thof trial initiation; b) need of res-
cue therapy during follow-up if average of HbA1c>6.5% or fasting glucose�7.0 mmol/l or 2h
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post load glucose�11.1 mmol/l in two consecutive study visits; c) any serious adverse event
(SAEs); d) voluntary drug discontinuation and/or withdrawn of the participant from the trial;
and e) pregnancy in a female participant during the trial. Despite of unmasking or drug dis-
continuation, lifestyle intervention and outcome assessments are carried out as originally
planned (intention to treat).
Study procedures
Assessment of primary outcomes. Diabetic Retinopathy is graded according to the final
ETDRS scale using digital fundus photographs. The photograph´s protocol was the one vali-
dated by the Joslin Vision Network (3 pictures covering posterior pole) performed under
mydriasis with tropicamide, and carried out by certified photographers. Retinal images were
sent to the reading centre at the IOBA (Eye Institute) of the University of Valladolid, Spain,
and graded by trained ophthalmologists who were blinded to the participant´s treatment
group assigned. Retinal findings were graded using the ETDRS [25].
Detection of distal small fiber nerve impairment was done measuring the peripheral nerve
conductance by the proxy sudomotor function with the SUDOSCAN device, a non-invasive
quantitative method based on the electrochemical reaction between sweat chlorides and stain-
less-steel electrodes in contact with the palm of the hands and soles of the feet. Results of nerve
conductance are given in micro-siemens (μS) for hands and feet. SUDOSCAN can detect distal
small fibre polyneuropathy with a sensitivity of>75%. The SUDOSCAN method has been val-
idated for the detection of sudomotor dysfunction [24–26]. Early diabetic peripheral neuropa-
thy is defined as a reduction of>1SD in the conductance values between two measurements.
Urine albumin and creatinine levels are measured from spot urine samples in the central
laboratory Fundacio´n Jime´nez Dı´az, Madrid. Microalbuminuria is defined as UACR of�30
mg/g; Clinical albuminuria is defined as UACR�300 mg/g. Glomerular filtration rate is esti-
mated by the Modification of Diet in Renal Disease (MDRD-4) Study equation, and by the
Chronic Kidney Disease Epidemiological Collaboration (CKD-EPI) equation [27].
The primary composite microvascular complication index is calculated using a linear com-
bination of the ETDRS score, the level of urinary albumin to creatinine ratio, and the SUDOS-
CAN index.
Assessment of secondary endpoints. Self-perceived quality of life with the EQ-5D-5L
instrument; symptoms of neuropathy are measured with the Michigan Neuropathy Screening
Instrument; symptoms of depression are recorded with the Hamilton Rating Scale for Depres-
sion (HAM-D) and the Mini-International Neuropsychiatric Interview (MINI) [28–31]. Cog-
nitive function is measured with the Montreal Cognitive Assessment (MOCA), Trail making
test A and B and Digit-Span forward and backward [32, 33].
Insulin secretion rates and β-cell glucose sensitivity are estimated by the slope of the insulin
secretion/plasma glucose dose-response by C-peptide deconvolution by OGTT modelling
[34]. Finally, in a random subsample of participants, the endothelial function with the Endo-
PAT1device, and novel biomarkers related to inflammation, microvascular function and non-
alcoholic fatty liver disease (NAFLD) will be also measured [35,36].
In addition to outcome assessment, at baseline each participant undergone a complete
medical interview, a physical activity assessment with the RPAQ questionnaire, and dietary
habits assessment with a food frequency questionnaire combining questions from two vali-
dated questionnaire [37–39].
Physical examination included body weight measurement (0.1 kg precision with calibrated
balance) and height (0.5 cm scale precision) in light indoor clothing without shoes; heart rate
was measured during one minute and blood pressure recorded twice with a mercury
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sphygmomanometer in both seated and standing position; waist and hip circumferences were
measured with a plastic tape (0.1 cm precision).
Biochemical determinations included an oral glucose tolerance test (OGTT) carried out
according to the WHO recommendations. A 300 ml test solution containing 75g of anhydrous
glucose and 1.6 g of citric acid was used. The OGTT started after 12 hours of fasting. Venous
blood samples were obtained after the ingestion of the glucose solution at min 0, 30, 60, 90 and
120. Samples were drawn into fluoridated tubes and centrifuged within 30 minutes. Plasma
glucose is determined locally in all samples with the HEMOCUE1 system. The aliquot sam-
ples from all point-time OGTT were shipped to the central laboratory for insulin and c-peptide
assays. Also HbA1c, serum total cholesterol (T-C), high-density lipoprotein (HDL-C), triglyc-
erides (TG), low density lipoprotein (LDL-C), AST, ALT, GGT, ALP, amylase, serum creati-
nine and uric acid concentrations were determined by usual standard methods at each local
laboratory. Complete assessments are repeated at month 24th.
The protocol is available at www.epredice.eu and registred at https://clinicaltrials.gov/ct2/
show/NCT03222765. For data entry and quality control, a specific web-based system under
open-source software Open Clinica1 was developed (https://community.openclinica.com).
Statistical analysis
This paper provides data on the screening, randomization and intention-to-treat processes.
Baseline descriptive results are only provided for people randomized and who accepted the
treatment assigned. The only comparative data provided are between the whole group of
patients who initiated treatment and those who refused to participate. Comparisons by treat-
ment arm are not provided in order to preserve randomization concealment, as the trial is still
ongoing. For this specific paper only descriptive statistics (mean, SD, percentages and 95%CI)
are reported. Comparisons between randomised & treated vs randomised & not-treated, after
randomization were done with the t-test for two independent samples and for comparisons of
proportions were done with the Pearson Chi-Squared test. Blinding of the randomised treat-
ments are maintained until the final database is closed and released for statistical analyses, after
all participants have completed the 24-month visit or have earlier discontinued study therapy.
No analyses of unmasked or between-group data will be performed before the database is
closed or released. All statistical analyses are performed by an independent statistics group.
Analysis of efficacy will be done both by intention-to treat (as randomised), and per protocol.
The primary analysis will compare complications in all three antidiabetic therapies com-
bined (metformin, linagliptin, and linagliptin with metformin), to complications in the life-
style only arm, to see whether further glucose lowering in the prediabetic state by antidiabetic
therapies reduces diabetic complications. It will also assess whether any of the active pharma-
cologic therapies separately has a superior effect compared to lifestyle intervention.
Analysis will be performed using Mann-Whitney U-test (two-sided, significance level 0.05)
or alternatively analysis of covariance (ANCOVA) in case adjustment for baseline variables is
required between the 3 active arms combined and the lifestyle arm. The analyses will be per-
formed on the intention to treat basis, with adjustments for baseline variables significantly dif-
fering between the groups and significantly related to the outcome variable.
An independent external Data Safety and Monitoring Committee (DSMC) was constituted
to oversee safety and to perform ongoing safety surveillance at pre-defined time points. The
DSMC evaluates all relevant safety information received, and has access to un-blinded data.
SAEs are assessed and classified by the DSMC. SAEs will be then encoded using the Medical
Dictionary for Regulatory Activities (Med DRA version 12.1) system. All SAEs are collected,
assessed and recorded by the local investigator as to the severity, possible relationship to the
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study medication and onset. This includes laboratory abnormalities, if considered an SAE by
the investigator. All SAEs will be tabulated in the statistical report as total, by severity adverse
events and if related to the study medication.
Ethical issues
Prior to any trial-related activity, the investigators gave verbal and written information about
the trial in a form that the participant could read and understand. A voluntary, personally
dated written informed consent form was signed by all study participants, prior to any trial-
related activity was started (form attached). The informed consent sheet complied with the
applicable regulatory European medical agency requirements, and adheres with the Interna-
tional Good Clinical Practice Guidelines, and the Helsinki Declaration.
The trial was registered in EUDRA-CT (ID 2013-000418-39) before the first patient was
recruited and after in the ClinicalTrials.gov (ID: NCT03222765). The main reasons for delay
in registering this study was Stopped during more than one year because financial problems
and bureaucracies with the EU. The participating clinical centres entered the study at different
times. At the very beginning the trial was only initiated in Spain. At this stage we were unable
to predict if the trial would stay only as a pilot trial, and how many of participating centres
identified in the EU proposal would be able to overcome these financial and administrative
barriers. During this process the coordinating centre and the CRO changed two times, 4 part-
ners withdrew the European Consortium, one of the drug companies compromised to donate
medication withdrew the consortium, and the EU delayed the funds during more than one
year and a half until all administrative local problems described were overcome. So we decided
do not register the trial in clinicaltrials.gov until we were sure the trial will continue, avoiding
early removal, continuous changes in the registration process, and unnecessary works. The
authors confirm that all ongoing and related trials for this drug/intervention are registered.
The clinical trial is currently ongoing, patients and data are being managed in a masked
fashion. Data cannot be made publicly available since data would compromise confidentialty
and might reveal identity or location of participants. Additionaly, public availability of data
would be in violation of the Spanish Organic Law 15/1999 of protection of personal data (con-
solidated text 5/3/2011) and the European Law (EU) 2016/679 from European Parlament and
European Council of 27 of April 2016 about Data Protection (RGPD).
The trial protocol was approved by all national Medicine Agencies and local ethic commit-
tees of participating centres:
• Comite´ E´tico de Investigacio´n Clı´nica del Hospital Universitario La Paz, Madrid, Spain.
Approval No. 3850 (01/02/2013).
• Hellenic Republic Ministry of Health National Ethics Committee, Greece. Approval No. 74/
00-01/14 (15/12/2014).
• The Dean office, Istanbul Medical Faculty Ethical Board for Clinical Trials, Turkey.-pproval
No. 2014/495 (10/04/2014).
• Etickog Odbora. Beograd, Republike Srbije, Serbia. Appoval No. 61/1 (06/04/2013).
• Ethics Committee of the Faculty of Medicine, University of Belgrade, Serbia. Approval No.
29/III-10(07/03/2013).
• Komisji Bioetycznej UJ (Uniwersytetu Jagiellonskiego), Poland. Appoval No. BET/185/L/
2014(26/06/2014).
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• Executive Officer of Ethics Review Committee (RPAH) & Human Research Ethics Commit-
tee (HREC), Australia. Approval No. X13-0046 & HREC/13/RPAH/65 (12/03/2014).
• комисия по етика "Александровска" ЕАД София, България, Bulgaria. Approval No. KИ-
213/18.03.15 (18/03/2015).
• Die Ethikkommission fu¨r das Bundesland Salzburg. "Landeskrankenhaus Salzburg-
• Universita¨tsklinikum der PMU, Universita¨tsklinik fu¨r Innere Medizin I", Austria. Approval
No. 415-E/1649/10-2014 (08/07/2014).
All study participants gave their written informed consent prior to the participation in the
study. The data Access Committee of Consejerı´a de Sanidad de la Comunidad de Madrid”ad-
dress: c/Plaza Carlos Trı´as Bertra´n n˚7 (Edif. Sollube) Madrid 28020; (protecciondedatos.sani-
dad@madrid.org) could consider those request that do not involve any conflict with these legal
regulations. Any acceptable request will be processed and alsoevaluated by the ePREDICE
Steering Committee.
The funders had no role in study design, data collection and analysis, decision to publish,
or preparation of the manuscript.
Results
Enrolment of the first patient first visit was on March 12, 2015, and the last patient first visit
was done on July 18, 2018 and the central database closed for this specific analysis. Recruit-
ment and clinical follow-up is still ongoing.
Fig 1 shows the study population flow-diagram. One thousand three hundred ninety one
potentially eligible adult individuals were screened using the standard OGTT; 424 (30.5%)
were excluded after screening: 318 (75%) out of them because did not meet the inclusion crite-
ria; 93 (21.9%) declined to sign the informed consent and 13 patients (3.1%) because other rea-
sons. Nine hundred and sixty seven patients (69.5% of those screened) were randomized (ITT
population) and 809 out of them (83.7%) started the assigned treatment. The flow-chart shows
also the number of patients initially allocated to each treatment group, and the number of
those who accepted and started the assigned treatment by study group as by July 18, 2018. The
92 randomized participants finally not included were allocated as follow: 27 to group 1; 24 to
group 2; 20 to group 3 and 21 to group 4. But the new flow-chart the 79 randomized partici-
pants finally not included were allocated as follow: 25 to group 1; 20 to group 2; 17 to group 3
and 17 to group 4. The sample was quite well balanced among all four groups, and no statistical
differences were observed in the allocation rate. The study is ongoing.
Table 1 shows the number and percentage of enrolled participants by centre by July 18,
2018. In Madrid, Spain a total of 323 were randomized and started treatment (39.9% of the
total final sample). The corresponding number of people randomized and treated by center
was 124 (15.3%) in Krakow, Poland; 84 (10.4%) in Malaga, Spain; 67 (8.3%) in Athens (NK),
Greece; 76 (9.4%) in Sofia, Bulgaria; 55 (6.8%) in Salzburg, Austria; 36 (4.4%) in Istanbul, Tur-
key; 44 (5.4%) in Belgrade (MSB), Serbia; Ongoing (NA) in Kuwait; Ongoing (NA) in Athens
(AH), Greece; Ongoing (NA) in Belgrade (UB), Serbia and Ongoing (NA) in Sydney,
Australia.
Table 2 shows preliminary data and compares means and standard deviations for key
demographic characteristics and major cardio-metabolic risk factors between people random-
ized who started treatment (n = 809), and those randomized who did not started treatment
(n = 79). No statistical differences were observed between the two groups for any of the vari-
ables analysed.
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Table 3 shows preliminary data the percentages of relevant clinical abnormalities at base-
line. Thirty four people (4.2%) shown DR>14 according to ETDRS; 43 people (5.3%) had
severe peripheral neuropathy according to SUDOSCAN criteria (feet ESC<50 μS or hand
ESC<40 μS), and 46 people (5.7%) had nephropathy at baseline with albuminuria levels >30
mg/dl.
Fig 1. ePREDICE CONSORT flow diagram baseline.
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Data from Kuwait (36 patients), Athens -AH- (17 patients), Belgrade -UB- (17 patients)
and Sydney (9 patients) are incomplete or unavailable at the moment. Therefore, these patients
were not included in the analyses performed.
Discussion
ePREDICE is an investigator-driven, independent clinical trial, assessing effects of different
glucose lowering drugs combined with lifestyle counselling on preservation of microvascular
function and early prevention of retinopathy, nephropathy and peripheral neuropathy in pre-
diabetic people. The trial is particularly innovative for the assessment of small nerve
impairment by using the sudomotor function with the Sudoscan device.
Microvascular complications appear at early stage of the disease, and are suitable as major
outcome when trying to prevent complications of hyperglycaemia. Our hypothesis is that
intensive and early treatment combining safe antidiabetic drugs with lifestyle intervention is
more effective than intensive lifestyle intervention alone in preventing microvascular compli-
cations in adults with non-diabetic hyperglycaemia range. The use of a particular antidiabetic
drug is based on its capacity to control glycaemia, and the likelihood to produce long-term
benefits, which is the key issue in pre-diabetes. We aim to investigate if the early and intensive
multifactorial treatment could challenge the current standard approach to pre-diabetes, using
pharmacological treatment as co-adjuvant to the lifestyle interventions. We also aim to see to
what extent, a more intensive preventive treatment can reduce the progression from pre-dia-
betes to diabetes. Previous studies have shown that lifestyle intervention and pharmacotherapy
reduces the risk of progression in people with IGT, but results among people with IFG have
been inconclusive. Our study can throw light to this open question [40, 41].
The trial´s recruitment process was quite efficient with a 30.5% rate of screening failure,
which is lower than those reported by other similar trials in the field [17]. The rate of accep-
tance of drug treatment (91.1%) is considered very high for a primary prevention trial with
Table 1. Number of people randomized and initiated treatment by study site in the ePREDICE trial. 1
Location Randomized n(%) Initiated the allocated study treatment n(%)
Madrid, Spain 349 (36.1) 323 (39.9)
Krakow, Poland 134 (13.9) 124 (15.3)
Ma´laga, Spain 90 (9.3) 84 (10.4)
Athens (NK), Greece 80 (8.3) 67 (8.3)
Sofia, Bulgaria 79 (8.2) 76 (9.4)
Salzburg, Austria 63 (6.5) 55 (6.8)
Istanbul, Turkey 49 (5.1) 36 (4.4)
Belgrade (MSB), Serbia 44 (4.6) 44 (5.4)
Kuwait 36 (3.7) -
Athens (AH), Greece 17 (1.8) -
Belgrade (UB), Serbia 17 (1.8) -
Sydney, Australia 9 (0.9) -
TOTAL 967 (100) 809 (100)
1) ePREDICE denotes: Early Prevention of Diabetes Complications in People with Hyperglycaemia in Europe.
� NK: National and Kapodistrian University of Athens. Greece.
� MSB: Medical System Beograd. Belgrade, Serbia.
� AH: Alexandra Hospital. University of Athens. Greece.
� UB: Faculty of Medicine, University of Belgrade. Serbia.
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drugs and lifestyle combined, where only 50% of eligible people invited usually accept [17].
The main reasons for drug treatment refusal in primary prevention trials of chronic such as
pre-diabetes including ours is the unawareness of suffering a health problem without symp-
toms, and the unwillingness to sign the informed consent or taking a masked drug. However,
the similar socio-demographic characteristics and clinical profile of those people randomized
who rejected or accepted the drug treatment, allows ruling out any risk of differential bias
towards the inclusion of people with either higher or lower risk than planned.
We have compared the distribution of key cardio-metabolic risk factors in the ePREDICE
population with pre-diabetic people recruited by the DE-PLAN study, an European program
of diabetes prevention using the Finnish Diabetes Risk Score (FINDRISC) for screening fol-
lowed of an OGTT, in the same age-group (45–74 years), and which was previously conducted
by several ePREDICE investigators at the same primary care settings [42]. Participants in the
ePREDICE trial are similar in terms of socio-demographic, cardio-metabolic and lifestyle pro-
file than the sub-sample of prediabetic people in the DE-PLAN. Pre-diabetic population in
ePREDICE and DE-PLAN shown similar fasting-and 2h PG levels. Therefore, we can conclude
that ePREDICE sample represent fairly well the adult pre-diabetic population who use public
primary care services across Europe [42].
Table 2. Demographics and the major cardiovascular risk factors at baseline of people randomized in the ePREDICE trial (treated and non-treated; Intention-To-
Treat population).
Key variables Randomized Not Treated (n = 79) Randomized Treated (n = 809) P-value
Females (%) 50 (63.3) 470 (58.1) 0.371
Smoking every day (%) 11 (13.9) 116 (14.3) 0.636
Family history of diabetes (%)
26 (32.9) 321 (39.7) 0.485
Use of antihypertensive drugs 26 (32.9) 325 (40.2) 0.208
Physical activity (30 min or more every day) 37 (46.8) 415 (51.3) 0.449
Vegetables, fruits or berries consumption (every day) 42 (53.2) 475 (58.7) 0.340
Age, years 59.4 (7.8) 58.5 (7.6) 0.327
BMI (kg/m2) 30.8 (5.2) 30.6 (5.0) 0.729
Waist circumference in males (cm) 105.4 (12.2) 105.8 (12.0) 0.594
Waist circumference in females (cm) 98.9 (13.3) 99.3 (11.7) 0.594
Systolic blood pressure (mmHg) 130 (15.7) 132 (17.2) 0.372
Diastolic blood pressure (mmHg)
78 (8.9) 82 (10.7) 0.150
Fasting plasma glucose (mmol/L) 6.4 (0.4) 6.4 (0.5) 0.323
2-hour plasma glucose (mmol/L) 7.9 (1.7) 8.1 (1.7) 0.382
Serum total cholesterol (mmol/L) 5.1 (1.6) 5.3 (1.1) 0.219
Serum HDL cholesterol (mmol/L) 1.4 (0.3) 1.4 (2.7) 0.930
Serum LDL cholesterol (mmol/L) 3.2 (0.8) 3.3 (0.9) 0.202
Serum triglycerides (mmol/L) 1.5 (1.6) 1.5 (0.9) 0.940
HbA1c (%) 5.8 (0.3) 5.8 (0.4) 0.545
eGFR CKD-EPI (mL/min per 1.73 m2) 93.7 (7.4) 93.8 (9.5) 0.884
FINDRISC Score 13.3 (4.1) 13.8 (4.1) 0.262
For categorical variables % is presented.
For continuous variables Mean (SD) are presented.
BMI: body mass index;HbA1c: glycated haemoglobin; eGFR CKD-EPI: estimated glomerular filtration rate based on Chronic Kidney Disease Epidemiology
Collaboration; FINDRISC: Finnish Diabetes Risk Score.
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Few studies have reported the prevalence of microvascular abnormalities in the pre-diabetic
population, and less have used validated and standardized methods of assessment. The DPP
trial used the same criteria for diabetic retinopathy evaluation (ETDRS and central grading),
and reported a slightly higher prevalence of retinopathy (7.9%) in a sub-sample of prediabetic
participants people who did not progressed to overt clinical diabetes after 3-year of follow-up
[21]. The prevalence of peripheral neuropathy in pre-diabetic populations has been reported
to be up to 15% depending of the method used, but data based on SUDOSCAN are scarce. The
prevalence of severe neuropathy in our sample was 5.3%. A recent population study in Finnish
men with high-risk of T2D reported up to 11% of mild or severe neuropathy [43, 44]. How-
ever, if we consider both severe and mild neuropathy together the prevalence raises up to 31%
using the SUDOSCAN criteria. The prevalence of nephropathy in our study according to a
level of albuminuria>30mg/dl was 5.7%, similar than the reported by Melsom et al in a sample
of pre-diabetics from the US general population [45].
Limitations
Our approach was similar to that used in other landmark trials of diabetes prevention which
compared metformin to lifestyle intervention and both arms were also evaluated separately
against placebo (US DPP). However, the DPP was unable to observe any benefit of lifestyle
intervention or metformin on microvascular complications [21]. The original planning of
ePREDICE duration is relatively short (2-years) due to the limitation of primary fund sources.
Nevertheless, we hope that we will be able to monitor the status of the study participants for a
longer period.
Our primary objective is to compare the primary outcome in all three anti-diabetic drug
arms combined (metformin, linagliptin, and linagliptin/metformin) with the lifestyle (placebo)
only arm. To increase trial´s power the three main outcomes have been combined in a com-
posite endpoint.
Table 3. Frequency of relevant health conditions at baseline in randomized (treated and not-treated individuals; Intention-To-Treat population).
Health Condition Randomized Not Treated (%)
(n = 79)
Randomized Treated (%)
(n = 809)
P-value
Glycaemia categories 0.311
Isolated IGT 16 (20.3) 226 (27.9)
Isolated IFG 36 (45.6) 317 (39.2)
IGT+ IFG combined 27 (34.2) 266 (32.9)
Hypertension (SBP� 140 mmHg or DBP� 90 mmHg or antihypertensive
drug use)
40 (50.6) 486 (60.1) 0.103
Hypercholesterolemia (Serum total cholesterol� 200 mg or lipid lowering
drug use)
51 (64.6) 536 (66.3) 0.761
Overweight (BMI 25–29 kg/m2) 22 (27.8) 223 (27.6) 0.957
Obesity (BMI� 30 kg/m2) 41 (51.9) 411 (50.8) 0.853
Abdominal obesity (Males: WC� 94 cm) 25 (37.3) 301 (42.9) 0.625
Abdominal obesity (Female: WC� 88 cm) 42 (62.7) 401 (57.1) 0.625
Diabetic Retinopathy (ETDRS > 14) 0 34 (4.2) NA
Severe neuropathy (feet ESC [μS]<50 or hands ESC [μS]<40) 2 (2.5) 43 (5.3) 0.282
Nephropathy (Albumin > 30 mg/dl) 2 (2.5) 46 (5.7) 0.237
IGT: Impaired Glucose Tolerance; IFG: Impaired Fasting Glucose; SBP: systolic blood pressure; DBP: diastolic blood pressure; BMI: body mass index; WC: waist
circumference; ETDRS: Early Treatment Diabetic Retinopathy Scale; NA: not applicable.
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Potential impact
ePREDICE final results will have the potential of changing the current paradigm of early man-
agement of intermediate hyperglycaemia and to guide treatment decisions in pre-diabetes.
The trial will permit the evaluation of effects of intensive treatment (lifestyle plus drug treat-
ment) in pre-diabetes for the early prevention of complication associated with hyperglycemia.
We also wish to characterize individuals who will develop early complications and to identify
which complication appears first. The follow-up will enable us to assess also the cumulative
incidence of various complications.
Conclusions
The ePREDICE is the first randomized clinical trial assessing effects of different interventions
(lifestyle and glucose lowering drugs together) on the prevention of microvascular complica-
tions and other outcomes in people with pre-diabetes. This approach can be also valuable to
investigate the mechanisms how to reduce microvascular complications by glucose lowering
drugs and lifestyle interventions. The ePREDICE study has proceeded well by collecting demo-
graphic, clinical information and complications associated with pre-diabetes at baseline.
Supporting information
S1 Table. Number of randomized and initiated treatment by study site.
(DOC)
S2 Table. Demographics and the major cardiovascular risk factors at baseline of people
randomized in the ePREDICE trial (treated and non-treated; Intention-To-Treat popula-
tion).
(DOC)
S3 Table. Frequency of relevant health conditions at baseline in randomized (treated and
not-treated individuals; Intention-To-Treat population).
(DOC)
S1 Checklist. CONSORT 2010 checklist of information to include when reporting a rando-
mised trial�.
(DOC)
S1 Data.
(PDF)
S2 Data.
(PDF)
S3 Data.
(PDF)
Acknowledgments
Members of the e-PREDICE Consortium.
Steering Committee: Jaakko Tuomilehto. Rafael Gabriel, Jaana Lindstro¨m, Jesu´s Egido.
Andrea Natali.
Jose´ Carlos Pastor, Michael Brainin, Marcus Lind, Luis Silva, Peter Schwartz, Aleksandra
Gilis. Uniwersytet Jagiellonski.
Safety Committee:
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Carmen Sua´rez Ferna´ndez. Hospital University La Princesa. Madrid, Spain.
Beberly Balkau. INSERM Veifville. France. Matti IJ Uusitupa. Institute of Public Health and
Clinical Nutrition. University of Eastern Finland. Kuopio, Finland.
Internal Ethic committee.
Julio Romero. Hospital University La Princesa. Madrid, Spain.
Lars Ryden. Karolinska Institute. Stockholm, Sweden.
External Scientific Advisory Board.
Ralph DeFronzo. University of Texas. San Antonio, Texas, USA. Manuel Serrano Rı´os. Uni-
versidad Complutense. Madrid, Spain. Michael Roden. German Center for Diabetes Research
(DZD). Mu¨nchen Neuherberg. Heinrich Heine University Du¨sseldorf, Du¨sseldorf, Germany.
John Nolan. European Diabetes Forum, European Association for the Study of Diabetes, Trin-
ity College Dublin, Ireland.
Work package (WP)
WP1: coordinador.
EVIDEM CONSULTORES Rafael Gabriel, Jaakko Tuomilehto.
Nisa Boukichou, Tania Acosta, Margarita Alonso, Ruy Lo´pez-Ridaura, Luis Silva, Eliana del
A´guila, Ana Roso´n.
WP2. CLINICAL CENTRES:
Spain.
Primary Care centres of SERMAS (Servicio Madrileño de Salud)
Toma´s Go´mez-Gasco´n, Juan Carlos Aba´nades Herranz, Marı´a Esther Sa´nchez Carranza,
Alicia Rodrı´guez Blanco, Fernando Villasante Claudios,Consuelo Ugarte Pe´rez, Bele´n Pela´ez
Raposo, Beatriz Ca´ceres Sa´nchez, Sergio Gonza´lez Gasca; Margarita Herrero Delgado, Isabel
Garcı´a Del Rı´o, Mª Lorena Rodrı´guez Pe´rez, Mª Carmen Reyes Madridejos, Mª Carmen Cas-
tillo Lo´pez, Mª Jesu´s Paloma Huerga Gonza´lez, Ana Alayeto Sa´nchez, Carmen Pascual Dı´ez,
Esperanza Villar Coloma, Tirso Galiano Arroyo, Mª Olga Peña Peña, Mª Elena Pejenaute
Labari, Mª Mercedes Rojo Tardo´n, Mª Teresa Recio Garcı´a, Marı´a Campos Lo´pez-Carrio´n,
Sara Criado Jorge, Virginia Garcı´a Campo, Almudena Pazos Gonza´lez, Aranzazu Pe´rez
Medina, Ricardo Benito Ferna´ndez, Mercedes Ricote Belincho´n, Mª Teresa Sa´nchez-Villares
Rodrı´guez, Noelia Polo Ferna´ndez, Antonio Cabrera Majada, Eva Marı´a Revuelta Marinez,
Itziar Va´zquez Carrio´n, Mª Nuria Ferna´ndez De Cano Martı´n, Manuel Gutie´rrez Cabanas,
Soledad Ferna´ndez Saavedra, Yolanda Jime´nez Aguilar, Mª A´ngeles Rodrı´guez Loarce, Emilia
Pedroche Morales, Teresa Nieto Monreal, Marı´a Begoña Herna´ndez Olivares, Carmen Dom-
ı´nguez Encinas, Ana Martı´nez-Cabrera Pela´ez, Mª Ine´s Casas Jime´nez, Pilar Pe´rez Egea, Con-
cepcio´n Espariz Campano, A´ngeles Brieva Garcı´a, Mª Azucena Saez Berlana, Carlos Casanova
Garcı´a, Mª Carmen Belincho´n Moya, Mª Dolores Parejo Pablos, Elisa Varona Lahuerta, Esther
Labrador Arranz, Mª A´ngeles Conde Llorente, Mª Teresa Go´mez Martı´nez, Milagros Vela´z-
quez Garcı´a, Mª Patrocinio Verde Gonza´lez, Mª Rosario Campo Martı´nez, Mª Rosario Del
A´lamo Gutie´rrez, Mª Victoria Cantera Urcı´a, Alejandra Gonza´lez Esteban, Laura Rodrı´guez
Cortizo, Sabrina Sosa Ale´s, Eva Torres Cantero, Idoia Baı´llo Peña, Tamara Garcı´a Lo´pez, Cris-
tina Calle Domı´nguez, Inmaculada Peña Sainz, Mª Antonia Minguito Lobos, Consuelo Via-
monte Andre´s, Francisco Manuel Garcı´a Garcı´a, Jose´ Marı´a Lobos Bejarano, Raquel Juez
Pimienta, Emiliana Villares Motino, Elvira Pe´rez Peñas, Silvia Jime´nez, Laura Manuyama
Pacaya, Carmen Morales Guevara, Carmen Melero Gonza´lez, Blanca Novella Arribas, Marta
Cuevas, Bele´n Sierra Garcı´a, Marta Ruiz, Amelia Gonza´lez Gamarra, Rosa Mª Sa´nchez Alcalde,
Bele´n Pela´ez Raposo, A´ngela Gallego Arenas, Mª Soledad Mayayo Vicente, Javier Lo´pez Gon-
za´lez, Manuel Jovino Arango Victoria, Ana Marı´a Santos Caballero, Isabel Jimeno, Juana Iri-
bertegui, Ramo´n Marı´a Salgado, Marı´a Olga Ortega de Santos, Marı´a Gema Garcı´a, Marı´a Jose´
LLore´ns Balducel, Juan Carlos de la Fuente, Claudia Ferna´ndez Illen, Beatriz Manrique
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Olmedo, Tati Are´valo Gallego, Juan Machuca Go´mez, Esther San Jose´ Bla´zquez, Teresa Caste-
llanos Ruiz, Macarena Espejo Saucedo, Marı´a Esther Ferna´ndez Yedra, Carmen Torres Martı´-
nez, A´ngel Lindo Torres, Vı´ctor Rau´l Montes Pina, khosrow Dadbin Dadbin, Rosa Arda´
Maillo, Inmaculada Parra A´lvarez, Justino Flores Ramos, Mª Dolores Vicente de Forondo,
Antonio Calvo Cebrian, Yolanda Gines Dı´az, Paloma Henares Garcı´a, Luı´s La Puente Mon-
toso, Aurora Lo´pez Gil, Mª Concepcio´n Marcello,Silvia Membrado Go´mez, Nieves Puente
Garcı´a, Nuria Rodrı´guez Pata, Antonio Sa´nchez Calso, Mª Sa´nchez Casado, Mª Pilar Saladana
Calzo, Carmen Velayos Rodrı´guez, Consuelo Velaz Lo´pez, Miguel A´ngel Venga Mendı´a, C.
Susana Abad Guijarro, Gema Calderero Castellanos, Esperanza Corral Agu¨ero, A´ngeles Fer-
na´ndez Ortega, Carmen Garcı´a Regidor, Edurne Herna´ndez Sanzano, Pablo Martı´n Cano, Mª
Del Carmen Martı´nez Coello, Sandrine Miguel Miguel, Mª Jesu´s Ramos Martı´n de Argenta,
Beatriz Ruescas Aurrecoechea, Esteban Gonza´lez Lo´pez, Elena Ramos Quiro´s, David Pe´rez
Mancho´n, Leticia Ponto´n, Jon Koldo Sagardui Villamor, Mireia Rey Pe´rez de Pipaon, Mª
Luisa Idarreta Zubiria, Juan Carlos Sa´nchez Ruiz, A´ngela Rodrı´guez de Cossio, Milagros
Merino Pella, Nuria Ruiz Hombrebueno, Rafael Llanes, Yolanda Vicente Prior, Mercedes
Pico´, Francisco Pe´rez Dura´n, Isabel Pe´rez Botella, A´ngeles Cuevas, Francisco Martı´nez Garcı´a,
Raquel Cobeñas Mateo, Marı´a Teresa Rodrı´guez De Fonseca, Naldi Luz Cerdeña Ocola, Irene
Alma Polanco Garcı´a, Marı´a Esther Amez De Castro, Susana Barrios Espinoza, Antonio Gui-
jarro Jime´nez, Ana Marı´a De La Uz Pardos, Francisco Javier Cabrera Pe´rez, Jose´ Ignacio Tor-
res Jime´nez, Francisco Martı´nez Garcı´a, Marı´a Isabel Vidal De La Riva, Marı´a Teresa
Rodrı´guez De Fonseca, Gabriel Barderas Cuevas, Gonzalo Carrillo De Albornoz Martı´nez Pan-
toja, Mª Isabel Garcı´a Romero.
Castilla y Leo´n.
Primary care centers of A´vila.
Primary Care centre of Are´valo: Saturio Vega Quiroga; Roberto Aldrich Garcı´a, Carlos
Cañas Ruesgas, Carmen Vian Baron, Josefina Ferna´ndez Ferna´ndez, Mª Antonia Jime´nez Car-
abias, Laureano Lo´pez Gay, Mª Pilar Marque´s Macı´as, Almudena Cantalejo Martı´n, Ana
Benito Pe´rez, Modesta Mulero San Jose´, Vanesa Martı´n Herna´ndez, Laura Sa´nchez Domı´n-
guez, Rosa Mª Garcı´a Martı´n, Victor Manuel A´lvarez Zurdo.
Primary Care centre of Sotillo de la Adrada: David A´lvarez Sua´rez, Carmen La´zaro del
Nogal, Lourdes Gonza´lez Lo´pez, Mª del Mar Varas Reviejo, Juan Luis Martı´n Clavo, Mª Isabel
Bla´zquez Blanco,Mª Luisa Ramos Gonza´lez, Guadalupe Rinaldi Català, Montserrat Lo´pez
Ramı´rez, Vanesa Herna´ndez Bla´zquez, Vanessa Gutie´rrez Leo´n, Raquel Pe´rez Cruz, Josefina
Ferna´ndez Ferna´ndez, Almudena Ferna´ndez Garcı´a, Raquel Alonso Moralejo.
Primary care centers of Segovia.
Primary Care centre of Carbonero El Mayor: Marı´a Soledad Fragua Gil, Virginia Silva
Guisasola, Concepcio´n Manrique de la Fuente, A´ngeles Lazcoz Fonta´n, He´ctor Aceves
Gamarra, Alba Marina Herna´ndez Lo´pez, Mª Jesu´s Blanco Ledesma, Alfonso Santos Lo´pez,
Cristina de la Cruz Maeso, Mª del Espı´ritu Santo Otero Herrero, Cristina Olmos Marinero,
Patricia Redondo Arranz, Mo´nica A´lvaro Garcı´a.
Primary Care centre of Segovia III: Luis Gonza´lvez Lo´pez, Marı´a A´ngeles Raquejo Grado,
Jose´ Rodrı´guez Sanz, Juan Manuel de Andre´s Rubio, Nuria Gonza´lez Acebes, Joaquina Gala´n
Sa´nchez, Teresa Lo´pez Ferna´ndez-Quesada, Almudena Sanz Prieto, Carmen Montero Mora-
les, Marı´a Dolores Alba Jime´nez, Beatriz Ayala Miranda.
Castilla-La Mancha.
Primary Care centres of CUENCA.
Hospital General: Jaime Santiago Aranda Regules, Alba Caterina del Hoyo Herra´iz, Marı´a
Victoria Cantero Ayllo´n, Marı´a Jose´ Guille´n Izquierdo, Marı´a Sandra Ruiz Mora, Ana Peña
Cabia, Rosa Sa´nchez Amo, M˚ Josefa Moya Lo´pez.
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Cuenca I: Fructuoso Muelas Herra´iz, M˚ A´ngeles Molina Morate, Fernando Salcedo
Aguilar.
Cuenca II: Nieves Valero Caracena, Beatriz Ortega Noheda, M˚ Carmen Garcı´a Gonza´lez.
Cuenca III: Cristina Martı´nez Martı´n, Miryam Pardo Villalvilla, Mª Eugenia Garcı´a Caste-
llanos, Marı´a Elena de las Heras Martı´nez.
Primary Care centre of Taranco´n: Filomena del Saz Castellanos, Encarnacio´n Palomares
Cañada, Marı´a Concepcio´n Fraile Jime´nez, Pilar Palomar Moreno, Ba´rbara Martı´nez Garrido,
Marı´a Pilar Orgaz Gallego, Marı´a Jose´ Tricio Armero, Cristina Garcı´a del Pino Cañadas, Isabel
Tierno Aparicio.
Ma´laga.
Fundacio´n FIMABIS. Servicio Andaluz de Salud (SAS)
Medicina Interna: Ricardo Go´mez-Huelgas, Marı´a Dolores Lo´pez-Carmona, Luis M
Pe´rez-Belmonte, Marı´a Rosa Bernal-Lo´pez, Marı´a Teresa Moyano Paris, Paula Moya Rodrı´-
guez, Antonio Vargas Candela, Alberto Vilches Pe´rez, Marı´a Isabel Ruiz Moreno, Maite
Muñoz Melero, Pilar Go´mez Martin.
Oftalmologı´a: Jacinto Villalvilla, A´lvaro Santos, Antonio Archilla, Carlos Rocha, Silvia
Lozano Ruiz.
Primary care centers of Ma´laga.
Alameda- Perchel: Francisco Javier Orellana Lozano, Manuel Guarino Nuño,
Alhaurı´n de la Torre: Daniel Martin Castillo, Marı´a Jose´ Guerra Maldonado, Jose´ Rogelio
Sa´nchez Ortiz.
Alozaina-Yunquera: David Ferna´ndez Bonilla, J A Cortes, Juan Antonio Cordero Cabrera.
Antequera: Jose´ Antonio Godı´nez, Jose´ Jesu´s Moreno Jime´nez, David Paniagua Urbano.
Archidona: Antonio Cansino Osuna, Marı´a Del Carmen Rojo Camacho, Celinda Lara
Moreno, Ignacio Hinojosa Nu´ñez, Almudena Puga Gonza´lez.
Capuchinos: Yolanda Rey, Yolanda Rodrı´guez Gallego.
Carranque: Carmen Aylo´n Moliner.
Cartama Estacion—Cartama pueblo-Pizarra: Francisco Jose Guirado Hidalgo, Marı´a Eva
Ruiz Coronado, Susana Barea Diañez, Beatriz Navarro Aranda.
Casarabonela: M Carmen Arroyo Martı´nez.
Ciudad Jardin: Antonio Baca Osorio, Jose´ Mancera, Salvador Ruiz Vera, Idelfonso Martos
Cerezuela.
Delicias:Fernando Lo´pez Verde, Mª Carmen Barba Cañete, Cristo´bal Go´mez Acevedo,
Margarita Sa´nchez Pavo´n.
La Luz: Antonio Oropez Mesa, Antonio Rojas Barrilado.
La Roca: Esther Martin Aurioles, Rocı´o Ramos, Francisco Javier Camino, Marı´a Eugenia
Valdes, Dolores Bravo Ferna´ndez.
Limonar: Silvia Hazañas, Amparo Vargas Machuca Benı´tez, Eva Marı´a Taboada Rı´os.
Puerta Blanca: Antonio Hormigo Pozo, Idelfonsa Martı´nez Zaragoza.
Rinco´n de la Victoria: Milagrosa Espinar Toledo, Marı´a Del Rosario Rosillo Rein, Gloria
Inmaculada Mestre Reoyo, Marı´a Auxiliadora Naranjo Sa´nchez, Jose´ A´ngel Sa´nchez Ortiz, Mª
Jose´ Gonza´lez Vega,
Jose´ Carlos Pe´rez Sa´nchez, Antonia Cabra Navarro, Antonio Vivas Molina.
San Andre´s-El torcal: Antonio Ramı´rez Ceballos, Francisco Ruiz Solares.
Tiro Picho´n: Juan Jose´ Bedoya Belmonte, Germa´n Ortega Nu´ñez, Marı´a Encarnacio´n
Bueno Caro.
Trinidad-Jesu´s cautivo: Santos Agreda.
Victoria: Marı´a Jose´ Bujalance Zafra, Montse Roma´n Cereto, Rafael A´ngel Maqueda.
Poland.
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Uniwersytet Jagiellonski, Collegium Medicum, Poland: Aleksandra Gilis-Januszewska,
Alicja Hubalewska-Dydejczyk, Beata Piwońska- Solska, Justyna Biegańska, Katarzyna
Cybulska, Bernadeta Marcykiewicz, Magdalena Duraczyńska, Anna Cybulska, Joanna Stankie-
wicz- Go´ra, Alina Mruk, Grzegorz Młyński, Lucyna Rozpondek, Michał Sroka, Maciej Gilis-
Januszewski, Edyta Sacha, Adela Justyńska,
Magdalena Szopa, Bartłomiej Matejko.
Greece.
National and Kapodistrian University of Athens. Greece: Konstantinos Makrilakis, Stav-
ros Liatis, Evangelia Siami, Chryssoula Stathi, Katerina Barmpagianni, Maria Nikoloudi, Mer-
opi Kontogianni, Ioanna Kechrimpari, Aphroditi Tsiakou, Melina Karaolia.
Alexandra Hospital. University of Athens. Greece: Asimina Mitrakou, Georgios Panago-
poulos, Paraskevi Kontou, Petros Thomakos, Georgios Giagkou, Evangelia Avgeraki, Eirini
Mamalaki.
Bulgaria.
University Multi-Profile Hospital for Active Treatment Alexandrovska EAD. Sofia, Bul-
garia: Zdravko Asenov Kamenov, Antoaneta Trifonova Gateva, Yavor Sashov Assyov, Tsvetan
Vladimirov Gatev, Vera Nacheva Karamfilova, Iveta Slavyanova Nedeva.
Austria.
Gemeinnutzige Salzburger Landeskliniken Betriebsgesellschaft. Salzburg, Austria:
Bernhard Paulweber, Ludmilla Kedenko, Andrea Undeutsch.
Turkey.
Istanbul University Istanbul. Turkey: Ilhan Satman, B. Fulya Turker, Ayse K. Uzum,
Sakin Tekin, Ramazan C¸akmak, Elif T. Bagdemir, Selda G. Celik, Cemile C. Idiz, Halime C.
Sackoparan, Zafer Cebeci.
Nur Kir, Dilara Karsidag, Yildiz Tutuncu, Aslihan Demirbas, Busra Yildiz.
Serbia.
Medical System Beograd-MSB. Belgrade, Serbia.
Predrag Djordjevic, Margarita Dodevska, Nevenka Raketic, Aleksandar Stamenkovic,
Marko Jovic, Fadil Canovic, Ljiljana Milivojevic, Kristina Savic, Ljiljana Savic, Mirjana Sarkic.
Faculty of Medicine, University of Belgrade. Serbia.
Nebojsa Lalic, Katerina Lalic, Aleksandra Jotic, Jelena Stanarcic.
Australia.
The Univerity of Sydney. Australia: Stephen Colagiuri, Anthony Keech, Kristine Mad-
dock, Andrzej S. Januszewski, Liping Lee, Tegan Picone, Emma Sainsbury, Alison Coenen,
Chelsea Hendy, Namson Lau.
Tania Markovic, Erica Bessell, Nick Fuller.
Kuwait.
Dasman Diabetes Research Institute: Jaakko Tuomilehto, Abdullah Alkandari, Abdullah
Bennakhi, Monira Alarouj, Mohammad Jalali, Medinella Fernandez, Michael Theodorakis,
Makka Ali Osman, Jincy Raj, Ala’a Al-Obaid.
WP3. Lifestyle Intervention.
Terveyden ja Hyvinvoinnin Laitos. Finland: Jaana Lindstro¨m, Pa¨ivi Valve, Katri Hemio¨,
Katja Wikstro¨m, Esko Leva¨lahti, Pirjo Saastamoinen.
WP4. Central laboratories and Biobank.
Instituto de Investigacio´n Sanitaria de la Fundacio´n Jime´nez Dı´az. Madrid, Spain (Cen-
tral Laboratory, Biobank and Inflammatory biomarkers): Jesu´s Egido, Sebastia´n Mas, San-
dra Zazo, Esther Civantos, Rosario de Nicola´s, Federico Rojo.
Consiglio Nazionale delle Ricerche. Pisa, Italy. (NAFLD laboratory): Amalia Gastaldelli,
Fabrizia Carli, Emma Buzzigoli, Melania Gaggini.
PLOS ONE Lifestyle and drug intervention for prevention of microvascular complications in pre-diabetes - ePREDICE.
PLOS ONE | https://doi.org/10.1371/journal.pone.0231196 April 13, 2020 18 / 23
Fundacio´ Hospital Universitari Vall d’ Hebron, Institut de Recerca. Barcelona, Spain
(Retinal biomarkers): Rafael Simo´, Cristina Herna´ndez, Marta Garcı´a-Ramirez.
Queen Mary University of London. UK (Genetic laboratory): Graham A Hitman.
WP5. Microvascular assessment coordination.
Universita di Pisa, Italy. (Endotelial assessment): Andrea Natali, Lucrecia Motta.
WP6. Retinal Assessment.
Instituto de Oftalmobiologı´a Aplicada (IOBA) Universidad de Valladolid, Spain. (Cen-
tral Retinal Reading Centre): Maribel Lo´pez, Jose´ Carlos Pastor, Lucı´a Manzanas, Ignacio
Alonso, Vero´nica Velasco, Laura Mena.
e-DIAGNOSTIC Oftalmologı´a. Madrid, Spain. (Retinal e-platform): Diana Bravo, Vı´c-
tor Gonza´lez Rumayor, Marica D´Angelo, A´lex Manau.
WP7. Neuropsychological assessment.
Department for Clinical Neurosciences and Preventive Medicine, Danube University
Krems. Krems, Austria: Michael Brainin, Yvonne Teuschl, Alexandra Dachenhausen, Karl
Matz.
Instituto de Investigacio´n y Asistencia Psiquia´trica (IAP). Madrid, Spain: Laura Fer-
rando Bundı´o.
Oivauni Oy. Kuopio,Finland: Henri Tuomilehto, Seppo Silvennoinen.
WP8. Statistical analysis.
Vastra Gotalands Lans Landsting. Gotenburg, Sweden (Statistical Analysis coordina-
tor): Marcus Lind, Aldina Pivodic, Hans Wedel.
Institute of Neuroscience, National Research Council (Consiglio Nazionale delle
Ricerche). Pavoda, Italy. (Insulin and C-Peptide modeling): Andrea Mari, Andrea Tura.
University of Helsinki. Department of Public Health: Pekka Jousilahti.
WP9. Technology Assessment.
IMPETO Medical. Paris, France (Sudoscan assessment): Jean-Henri Calvet, GaelleLerise,
Alice Vilier.
Mezen Bouzaien.
AARDEX Group SA. Geneva. Switzerland (MEMs drug´s adherence monitoring): Ber-
nard Vrijens, Rodrigo Paiva, Eric Tousset.
WP10. Dissemination and communication:
Federation Internationale du Diabete Region Europe AISBL: Lala Rabemananjara.
Author Contributions
Conceptualization: Rafael Gabriel, Jaakko Tuomilehto.
Data curation: Rafael Gabriel, Nisa Boukichou Abdelkader, Tania Acosta, Jaakko Tuomilehto.
Formal analysis: Rafael Gabriel, Nisa Boukichou Abdelkader, Tania Acosta, Jaakko
Tuomilehto.
Funding acquisition: Rafael Gabriel, Jaakko Tuomilehto.
Investigation: Rafael Gabriel, Aleksandra Gilis-Januszewska, Ricardo Go´mez-Huelgas, Kon-
stantinos Makrilakis, Zdravko Kamenov, Bernhard Paulweber, Ilhan Satman, Predrag
Djordjevic, Abdullah Alkandari, Asimina Mitrakou, Nebojsa Lalic, Stephen Colagiuri,
Jaana Lindstro¨m, Jesu´s Egido, Andrea Natali, J. Carlos Pastor, Yvonne Teuschl, Marcus
Lind, Luis Silva, Ruy Lo´pez-Ridaura, Jaakko Tuomilehto.
Methodology: Rafael Gabriel, Nisa Boukichou Abdelkader, Tania Acosta, Aleksandra Gilis-
Januszewska, Ricardo Go´mez-Huelgas, Konstantinos Makrilakis, Zdravko Kamenov,
PLOS ONE Lifestyle and drug intervention for prevention of microvascular complications in pre-diabetes - ePREDICE.
PLOS ONE | https://doi.org/10.1371/journal.pone.0231196 April 13, 2020 19 / 23
Bernhard Paulweber, Ilhan Satman, Predrag Djordjevic, Abdullah Alkandari, Asimina
Mitrakou, Nebojsa Lalic, Stephen Colagiuri, Jaana Lindstro¨m, Jesu´s Egido, Andrea Natali, J.
Carlos Pastor, Yvonne Teuschl, Marcus Lind, Luis Silva, Ruy Lo´pez-Ridaura, Jaakko
Tuomilehto.
Project administration: Rafael Gabriel, Nisa Boukichou Abdelkader, Tania Acosta, Jaakko
Tuomilehto.
Resources: Rafael Gabriel, Tania Acosta, Aleksandra Gilis-Januszewska, Ricardo Go´mez-
Huelgas, Konstantinos Makrilakis, Zdravko Kamenov, Bernhard Paulweber, Ilhan Satman,
Predrag Djordjevic, Abdullah Alkandari, Asimina Mitrakou, Nebojsa Lalic, Stephen Cola-
giuri, Jaana Lindstro¨m, Jesu´s Egido, Andrea Natali, J. Carlos Pastor, Yvonne Teuschl, Mar-
cus Lind, Luis Silva, Ruy Lo´pez-Ridaura, Jaakko Tuomilehto.
Software: Rafael Gabriel, Nisa Boukichou Abdelkader, Tania Acosta, Jaakko Tuomilehto.
Supervision: Rafael Gabriel, Nisa Boukichou Abdelkader, Tania Acosta, Aleksandra Gilis-
Januszewska, Ricardo Go´mez-Huelgas, Konstantinos Makrilakis, Zdravko Kamenov, Bern-
hard Paulweber, Ilhan Satman, Predrag Djordjevic, Abdullah Alkandari, Asimina Mitra-
kou, Nebojsa Lalic, Stephen Colagiuri, Jaana Lindstro¨m, Jesu´s Egido, Andrea Natali, J.
Carlos Pastor, Yvonne Teuschl, Marcus Lind, Luis Silva, Ruy Lo´pez-Ridaura, Jaakko
Tuomilehto.
Validation: Rafael Gabriel, Nisa Boukichou Abdelkader, Tania Acosta, Aleksandra Gilis-
Januszewska, Ricardo Go´mez-Huelgas, Konstantinos Makrilakis, Zdravko Kamenov, Bern-
hard Paulweber, Ilhan Satman, Predrag Djordjevic, Abdullah Alkandari, Asimina Mitra-
kou, Nebojsa Lalic, Stephen Colagiuri, Jaana Lindstro¨m, Jesu´s Egido, Andrea Natali, J.
Carlos Pastor, Yvonne Teuschl, Marcus Lind, Luis Silva, Ruy Lo´pez-Ridaura, Jaakko
Tuomilehto.
Visualization: Rafael Gabriel, Nisa Boukichou Abdelkader, Tania Acosta, Aleksandra Gilis-
Januszewska, Ricardo Go´mez-Huelgas, Konstantinos Makrilakis, Zdravko Kamenov, Bern-
hard Paulweber, Ilhan Satman, Predrag Djordjevic, Abdullah Alkandari, Asimina Mitra-
kou, Nebojsa Lalic, Stephen Colagiuri, Jaana Lindstro¨m, Jesu´s Egido, Andrea Natali, J.
Carlos Pastor, Yvonne Teuschl, Marcus Lind, Luis Silva, Ruy Lo´pez-Ridaura, Jaakko
Tuomilehto.
Writing – original draft: Rafael Gabriel, Nisa Boukichou Abdelkader, Tania Acosta, Jaakko
Tuomilehto.
Writing – review & editing: Rafael Gabriel, Nisa Boukichou Abdelkader, Tania Acosta, Alek-
sandra Gilis-Januszewska, Ricardo Go´mez-Huelgas, Konstantinos Makrilakis, Zdravko
Kamenov, Bernhard Paulweber, Ilhan Satman, Predrag Djordjevic, Abdullah Alkandari,
Asimina Mitrakou, Nebojsa Lalic, Stephen Colagiuri, Jaana Lindstro¨m, Jesu´s Egido, Andrea
Natali, J. Carlos Pastor, Yvonne Teuschl, Marcus Lind, Luis Silva, Ruy Lo´pez-Ridaura,
Jaakko Tuomilehto.
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