Extreme Phenotypes to Identify Susceptibility of Patients Living With Type 2 to Diabetes Related Complications (EXTREME-T2D)

November 23, 2025 updated by: Andrea Natali, Azienda Ospedaliero, Universitaria Pisana

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:

  • 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.

Study Overview

Status

Active, not recruiting

Conditions

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 Type

Observational

Enrollment (Estimated)

1000

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
    • BA
      • Bari, BA, Italy, 70100
        • Policlinico Consorziale di Bari
    • CT
      • Catania, CT, Italy, 95100
        • Azienda Rilievo Nazionale Alta Specialità (ARNAS) Garibaldi
    • PI
      • Pisa, PI, Italy, 56120
        • Azienda Ospedaliero Universitaria Pisana

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

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.

Description

Inclusion Criteria:

  • Type 2 Diabetes
  • Age 40-80 years old
  • Comprehensive screening for DRC within 24 months from the inclusion in the survey.

Exclusion Criteria:

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
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 the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
through study completion, an average of 12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
DRC score
Time Frame: Through study completion, an average of 12 months
To test the power of the designed score in categorizing patients for the diverse susceptibility to DRC
Through study completion, an average of 12 months
Biomarkers
Time Frame: through study completion, an average of 12 months
To select biomarkers for DRC susceptibility
through study completion, an average of 12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Azienda Ospedaliero, Universitaria Pisana

Investigators

  • Principal Investigator: Andrea Natali, MD, University of Pisa

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2024

Primary Completion (Estimated)

November 30, 2025

Study Completion (Estimated)

July 31, 2026

Study Registration Dates

First Submitted

November 17, 2025

First Submitted That Met QC Criteria

November 23, 2025

First Posted (Actual)

November 26, 2025

Study Record Updates

Last Update Posted (Actual)

November 26, 2025

Last Update Submitted That Met QC Criteria

November 23, 2025

Last Verified

November 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EXTREME-T2D phase 1

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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