Diabete Type 2EXTREME-T2DNCT07250607
Extreme Phenotypes to Identify Susceptibility of Patients Living With Type 2 to Diabetes Related Complications
An observational study of Diabete Type 2 and Diabetes Complications, run by Azienda Ospedaliero, Universitaria Pisana at 3 sites in Italy.
Trial summary
The goal of this observational study is to learn more about the diverse susceptibility to micro and macrovascular complications in individuals living with Type 2 Diabetes (T2D). The main questions of the study are: Is the chronic exposure to hyperglycemia the only determinant of diverse susceptibility to diabetes… Read more about this study
- Who is it for?
- Ages 40 to 80 years
- Conditions the study is for
- Diabete Type 2, Diabetes Complications
- How many people
- 1,000 participants
- Where
- 3 sitesItaly
- Study dates
- 1 May 2024to 31 Jul 2026
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Either sex, age between 40 and 80 years old. Diagnosed Type 2 diabetes (proven of exclusion of other forms diabetes if required by the PI) followed up regularly for T2D and with a comprehensive screening for complications including data on coronary, cerevrovascular and peripheral artery disease, and informations about chronic kidney, retinopathy and neuropathy diseases related to diabetes.
Who may be able to join
- Type 2 Diabetes
- Age 40-80 years old
- Comprehensive screening for DRC within 24 months from the inclusion in the survey.
Who cannot join
- Diagnosis of forms of diabetes other than T2D
- Any chronic inflammatory diseases or active cancer
- Significant liver disfunction (cirrhosis, AST/ALT > 3-fold normality range, total bilirubin > 1,5-fold normal range w/o Gilbert syndrome)
- Any other life expectancy-changing systemic disease.
Trial locations and contacts
3 sites in 1 country.
Italy3 sites
Policlinico Consorziale di Bari
Bari, BA, 70100
Azienda Rilievo Nazionale Alta Specialità (ARNAS) Garibaldi
Catania, CT, 95100
Azienda Ospedaliero Universitaria Pisana
Pisa, PI, 56120
About this study
Official title: Extreme Phenotypes to Identify the Patients With Type 2 Diabetes Who Are Susceptible or Resistant to Complications and to Reveal the Mechanisms
The goal of this observational study is to learn more about the diverse susceptibility to micro and macrovascular complications in individuals living with Type 2 Diabetes (T2D).
The main questions of the study are:
Read more
- Is the chronic exposure to hyperglycemia the only determinant of diverse susceptibility to diabetes related complications (DRC) across the T2D population?
- Is it possible to develop a reliable tool to identify patients at different susceptibility to DRC?
- Is it possible to predict DRC susceptibility through biomarkers in the field of inflammation, hormonal signaling or non-coding circulating nucleotides.
People living with T2D and well screened for complications according to the international recommendations (American Diabetes Association/European Society for the study of Diabetes) will be included in the survey collecting information about chronic exposure to hyperglycemia (diabetes duration + glycemic control) and incidence and severity of each macro and microvascular complication.
Based on the survey result, a clinical score will be proposed to distinguish patient at different susceptibility to complications.
Then, patients with extreme phenotypes of susceptibility (i.e. those with highest susceptibility for their short exposure to hyperglycemia vs those with lowest susceptibility to complication for their long exposure to hyperglycemia) will be recruited to perform a blood drawn and investigate whether preidentified potential biomarkers could describe the diverse susceptibility to DRC by showing a significant gradient between groups.
Read the detailed description
The incidence of diabetes related complications (DRC) in individuals living with type 2 diabetes (T2D) is known to depend on exposure to disease and risk factor control, but it displays a large interindividual variability. In this observational trial we will explore the feasibility to develop a method to estimate the degree of susceptibility to DRC in any single patient living with T2D, based on a standardized clinical assessment.
The study will consist in a systematic review of the clinical records of patients with T2D, referring 4 different diabetes clinics in Italy and Greece, who undergo a regular follow up and a complete assessment for DRC pertaining to 3 major macrovascular (coronary, cerebrovascular and peripheral) and 3 major microvascular (retina, kidney and peripheral nerves) districts. The diseases will be classified as a overt or subclinical in relation to their clinical significance. The clinical criteria for the classification will be standardized across the centers.
The final population (target= 1000 patients) will be then used to test the ability of a score (DRC score) to categorize each individual in a specific subgroup for DRC burden, that reflects the DRC susceptibility.
The DRC score has been designed by a consensus of expert, and calculated as the sum of each overt (3 points) and subclinical (1 point) micro- and macrovascular complication.
By applying the DRC score to the general T2D population referring to the study centers, we expect to select 120 subject with high susceptibility to complications (HS-DRC) and 120 subject with low susceptibility to complications (LS-DRC). These subject will undergo a blood drawn and full characterization of risk factors to test the ability of these biomarkers in predicting complications occurrence, when compared with a control population of T2D patients with moderate susceptibility to complications.
The potential biomarkers identified after a systematic review of the literature will be:
Environmental and lifestyle modulators: Smoke load; Fluctuations of body mass index (BMI), HbA1C, Blood pressure, lipid profile, kidney function; physical activity; diet quality; sleep quality.
Biological modulators of damage: IGF1, insulin, testosterone, leptin, glucagon; circulating non-coding microRNA related to diabetes complications.
Biological transducers of damage: hsCRP (high sensitivity C reactive proteine), interleukin-6, -1beta and -18, tumor necrosis factor alfa, tumor growth factor beta; carboxyl methyl-lysine, pentosidine; total antioxidant capacity, 3-nitrotyrosines, malondialdehyde.
Will be selected as biomarkers with predictive potential for DRC susceptibility all biomarkers showing a clear and unidirectional gradient between the two extreme phenotypes selected by using the proposed DRC score.
- Conditions
- Diabete Type 2, Diabetes Complications
- Keywords
- microvascular complications, macrovascular complications, Type 2 Diabetes Mellitus, Cardiovascular diseases
- Medical subject headings
- Diabetes Mellitus, Type 2, Diabetes Complications, Cardiovascular Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Subject with Highest susceptibility to complications (HS-DRC) | Subjects showing a number of diabetes related complication higher than expected compared with other subject with similar disease duration and glycemic control | |
| Subject with lowest susceptibility to complications (LS-DRC) | Subjects showing a number of diabetes related complication lower than expected compared with other subject with similar disease duration and glycemic control | |
| Subject with moderate susceptibility to complications (MS-DRC or control gtoup) | Subjects showing a number of diabetes related complication that is expected for their disease duration and glycemic control according to the DRC distribution in the general T2D population |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of Diabetes Related Complications.
to measure the incidence and intensity of each included micro and macrovascular complication
Measured: through study completion, an average of 12 months
Secondary outcomes (2)
DRC score
To test the power of the designed score in categorizing patients for the diverse susceptibility to DRC
Measured: Through study completion, an average of 12 months
Biomarkers
To select biomarkers for DRC susceptibility
Measured: through study completion, an average of 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Nov 2025
- Study start1 May 2024
- Primary completion30 Nov 2025 (estimated)
- Study completion31 Jul 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Diabete Type 2Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Retrospective
- Enrolment
- 1,000 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Azienda Ospedaliero, Universitaria Pisana
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Andrea Natali, Azienda Ospedaliero, Universitaria Pisana
- Investigators
- Andrea Natali, MD, Principal investigator, University of Pisa
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07250607
- Sponsor's protocol ID
- EXTREME-T2D phase 1
- Acronym
- EXTREME-T2D
- Status last verified
- Nov 2025
- First submitted
- 17 Nov 2025
- Last updated
- 26 Nov 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Sacchetta L, Gallo S, Chiriaco M, Tumino D, Carrubba N, Caruso I, Di Molfetta S, Anastasiou IA, Tentolouris N, Rebelos E, Fignani D, Sebastiani G, Dotta F, Giorgino F, Laviola L, Frittitta L, Solini A, Natali A. Quantifying the individual disease duration-adjusted burden of complications in persons with type 2 diabetes. Nutr Metab Cardiovasc Dis. 2026 Aug;36(8):104716. doi: 10.1016/j.numecd.2026.104716. Epub 2026 Mar 25.
PubMed 42000246
Study at a glance
From the registry record, last updated by the sponsor on 26 Nov 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Extreme Phenotypes to Identify the Patients With Type 2 Diabetes Who Are Susceptible or Resistant to Complications and to Reveal the Mechanisms
- ClinicalTrials.gov ID
- NCT07250607
- Acronym / sponsor ID
- EXTREME-T2D / EXTREME-T2D phase 1
- Conditions
- Diabete Type 2, Diabetes Complications
- Keywords
- microvascular complications, macrovascular complications, Type 2 Diabetes Mellitus, Cardiovascular diseases
- Study type
- Observational
- Recruitment status
- Active, not recruiting
- Enrolment
- 1,000 participants (estimated)
- Lead sponsor
- Azienda Ospedaliero, Universitaria PisanaUniversity, hospital or other
- Study start
- 1 May 2024 (actual)
- Primary completion
- 30 Nov 2025 (estimated)
- Study completion
- 31 Jul 2026 (estimated)
- First posted
- 26 Nov 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The goal of this observational study is to learn more about the diverse susceptibility to micro and macrovascular complications in individuals living with Type 2 Diabetes (T2D).
The main questions of the study are:
- Is the chronic exposure to hyperglycemia the only determinant of diverse susceptibility to diabetes related complications (DRC) across the T2D population?
- Is it possible to develop a reliable tool to identify patients at different susceptibility to DRC?
- Is it possible to predict DRC susceptibility through biomarkers in the field of inflammation, hormonal signaling or non-coding circulating nucleotides.
People living with T2D and well screened for complications according to the international recommendations (American Diabetes Association/European Society for the study of Diabetes) will be included in the survey collecting information about chronic exposure to hyperglycemia (diabetes duration + glycemic control) and incidence and severity of each macro and microvascular complication.
Based on the survey result, a clinical score will be proposed to distinguish patient at different susceptibility to complications.
Then, patients with extreme phenotypes of susceptibility (i.e. those with highest susceptibility for their short exposure to hyperglycemia vs those with lowest susceptibility to complication for their long exposure to hyperglycemia) will be recruited to perform a blood drawn and investigate whether preidentified potential biomarkers could describe the diverse susceptibility to DRC by showing a significant gradient between groups.
Detailed description
The incidence of diabetes related complications (DRC) in individuals living with type 2 diabetes (T2D) is known to depend on exposure to disease and risk factor control, but it displays a large interindividual variability. In this observational trial we will explore the feasibility to develop a method to estimate the degree of susceptibility to DRC in any single patient living with T2D, based on a standardized clinical assessment.
The study will consist in a systematic review of the clinical records of patients with T2D, referring 4 different diabetes clinics in Italy and Greece, who undergo a regular follow up and a complete assessment for DRC pertaining to 3 major macrovascular (coronary, cerebrovascular and peripheral) and 3 major microvascular (retina, kidney and peripheral nerves) districts. The diseases will be classified as a overt or subclinical in relation to their clinical significance. The clinical criteria for the classification will be standardized across the centers.
The final population (target= 1000 patients) will be then used to test the ability of a score (DRC score) to categorize each individual in a specific subgroup for DRC burden, that reflects the DRC susceptibility.
The DRC score has been designed by a consensus of expert, and calculated as the sum of each overt (3 points) and subclinical (1 point) micro- and macrovascular complication.
By applying the DRC score to the general T2D population referring to the study centers, we expect to select 120 subject with high susceptibility to complications (HS-DRC) and 120 subject with low susceptibility to complications (LS-DRC). These subject will undergo a blood drawn and full characterization of risk factors to test the ability of these biomarkers in predicting complications occurrence, when compared with a control population of T2D patients with moderate susceptibility to complications.
The potential biomarkers identified after a systematic review of the literature will be:
Environmental and lifestyle modulators: Smoke load; Fluctuations of body mass index (BMI), HbA1C, Blood pressure, lipid profile, kidney function; physical activity; diet quality; sleep quality.
Biological modulators of damage: IGF1, insulin, testosterone, leptin, glucagon; circulating non-coding microRNA related to diabetes complications.
Biological transducers of damage: hsCRP (high sensitivity C reactive proteine), interleukin-6, -1beta and -18, tumor necrosis factor alfa, tumor growth factor beta; carboxyl methyl-lysine, pentosidine; total antioxidant capacity, 3-nitrotyrosines, malondialdehyde.
Will be selected as biomarkers with predictive potential for DRC susceptibility all biomarkers showing a clear and unidirectional gradient between the two extreme phenotypes selected by using the proposed DRC score.
Study design
- Observational model
- Cohort
- Time perspective
- Retrospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Subject with Highest susceptibility to complications (HS-DRC) | – | –Subjects showing a number of diabetes related complication higher than expected compared with other subject with similar disease duration and glycemic control |
| Subject with lowest susceptibility to complications (LS-DRC) | – | –Subjects showing a number of diabetes related complication lower than expected compared with other subject with similar disease duration and glycemic control |
| Subject with moderate susceptibility to complications (MS-DRC or control gtoup) | – | –Subjects showing a number of diabetes related complication that is expected for their disease duration and glycemic control according to the DRC distribution in the general T2D population |
Who may qualify
- Ages
- 40 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Either sex, age between 40 and 80 years old. Diagnosed Type 2 diabetes (proven of exclusion of other forms diabetes if required by the PI) followed up regularly for T2D and with a comprehensive screening for complications including data on coronary, cerevrovascular and peripheral artery disease, and informations about chronic kidney, retinopathy and neuropathy diseases related to diabetes.
Key inclusion criteria (3 listed)
- Type 2 Diabetes
- Age 40-80 years old
- Comprehensive screening for DRC within 24 months from the inclusion in the survey.
Key exclusion criteria (4 listed)
- Diagnosis of forms of diabetes other than T2D
- Any chronic inflammatory diseases or active cancer
- Significant liver disfunction (cirrhosis, AST/ALT > 3-fold normality range, total bilirubin > 1,5-fold normal range w/o Gilbert syndrome)
- Any other life expectancy-changing systemic disease.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Incidence of Diabetes Related Complications.
Time frame: through study completion, an average of 12 months
to measure the incidence and intensity of each included micro and macrovascular complication
2 secondary outcomes
DRC score
Time frame: Through study completion, an average of 12 months
Biomarkers
Time frame: through study completion, an average of 12 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Nov 2025.
- Derived from this study: PubMed 42000246Sacchetta L, Gallo S, Chiriaco M, Tumino D, Carrubba N, Caruso I, Di Molfetta S, Anastasiou IA, Tentolouris N, Rebelos E, Fignani D, Sebastiani G, Dotta F, Giorgino F, Laviola L, Frittitta L, Solini A, Natali A. Quantifying the individual disease duration-adjusted burden of complications in persons with type 2 diabetes. Nutr Metab Cardiovasc Dis. 2026 Aug;36(8):104716. doi: 10.1016/j.numecd.2026.104716. Epub 2026 Mar 25.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Andrea Natali, MD principal investigator
University of Pisa
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Diabete Type 2 and Diabetes Complications, run by Azienda Ospedaliero, Universitaria Pisana at 3 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 26 Nov 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of Diabetes Related Complications. (time frame: through study completion, an average of 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07250607, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Nov 2025.