Adipose Tissue Heterogeneity and Its Link to Type 2 Diabetes (DiaSpax)

Adipose Tissue Heterogeneity and Its Link to Type 2 Diabetes: A Randomized Open Intervention Study That Compares Empagliflozin, Pioglitazone and Semaglutide

People with newly diagnosed type 2 diabetes treated with metformin that have not reached their HbA1c target (49-64 mmol/mol) will be recruited to the study. If they fulfill the inclusion and none of the exclusion criteria, they will be, after signing informed consent, randomized to a six-month intervention with either pioglitazone, empagliflozin or semaglutide. Fat biopsies are obtained from the subcutaneous abdominal area before and after a hyperinsulinemic-euglycemic clamp at baseline and after six months. Participants are regularly followed during this the intervention. The overall goal is to determine how antidiabetic-drugs affect white adipose tissue cellularity and whether adipose heterogeneity impacts on drug response. The primary outcome measure is the change in fat tissue lipolysis (glycerol release in isolated fat cells after hormone stimulation) before and after treatment.

Study Overview

• Status: Recruiting
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Pioglitazone 45 mg; Drug: Empagliflozin 25 MG; Drug: Semaglutide 7 MG

Detailed Description

A detailed description of the protocol has been approved by the Swedish Medical Products Agency and the study is registered as EudraCT: 2021-002367-21.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mikael Ryden, MD, PhD; Phone Number: +46736995215; Email: mikael.ryden@ki.se
• Study Contact Backup: Name: Jesper Bäckdahl, MD, PhD; Phone Number: +46702297237; Email: jesper.backdahl@ki.se

Study Locations

• Sweden
  • Stockholm, Sweden, 14186
    • Recruiting
    • Karolinska University Hospital
    • Contact: Jesper Bäckdahl, MD, PhD; Phone Number: +46702297237; Email: jesper.backdahl@ki.se
    • Contact: Mikael Rydén, MD, PhD; Phone Number: 0736995215; Email: mikael.ryden@ki.se
    • Sub-Investigator: Niklas Mejhert, PhD
    • Sub-Investigator: Daniel P Andersson, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signed informed consent
• BMI 27-35 kg/m2
• HbA1c 48 mmol/mol or higher
• For fertile women, effective contraception

Exclusion Criteria:

• HbA1c 65 mmol/mol or higher
• Established cardiovascular disease and/or heart failure
• Severe psychiatric condition
• Active alcoholism
• Insulin treatment
• Anticoagulant therapy (vitamin K antagonists or equivalent)
• Pregnancy, lactation
• Positive GAD or IA2 antibodies
• Low C-peptide/glucose ratio (less than 2 measured as pmol/mg per dL)
• NT-proBNP above the upper normal reference value
• Kidney disease
• Liver disease or hepatic values over twice the upper reference value
• Severe concomitant disease including ongoing cancer

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Pioglitazone; Pioglitazone is known to affect fat cells and is used as an active comparator. It reduces HbA1c but increase fat mass slightly. We hypothesize that pioglitazone may have particular benefits in individuals with a specific adipose cellularity.	Drug: Pioglitazone 45 mg; Starts with 45 mg
Experimental: Empagliflozin; Empagliflozin reduces HbA1c and increase lipolysis possibly due to increased glucagon secretion. It also reduces fat mass weight to a minor degree.	Drug: Empagliflozin 25 MG; Starts with 25 mg
Experimental: Semaglutide; Semaglutide reduces body weight, including fat mass, to a more significant degree than empagliflozin but has no known direct effects on adipose tissue.	Drug: Semaglutide 7 MG; Starts with 3 mg daily for the first 2 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in fat cell lipolysis after 6 months of treatment	Change in isoprenaline-induced (over basal) lipolysis in isolated fat cells	Baseline and after six months intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in fat cell heterogeneity after 6 months of treatment	Changes in the adiponectin/leptin mRNA expression ratio in adipose tissue measured by quantitative PCR	Baseline and after six months intervention

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in tissue cellularity after 6 months of treatment (explorative outcome)	Changes in adipose tissue cellularity measured by single-cell transcriptomic analyses of fat tissue biopsies	Baseline and after six months intervention

Collaborators and Investigators

• Sponsor: Karolinska Institutet
• Collaborators: Karolinska University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 8, 2023
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): December 31, 2032

Study Registration Dates

• First Submitted: August 10, 2022
• First Submitted That Met QC Criteria: August 11, 2022
• First Posted (Actual): August 15, 2022

Study Record Updates

• Last Update Posted (Actual): October 3, 2023
• Last Update Submitted That Met QC Criteria: October 2, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Pioglitazone; Empagliflozin
• Other Study ID Numbers: Karolinska University Hospital; 2021-002367-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: According to the ethical approval, we are not allowed to share participant data that can allow identification of the individual participants. We will present data at a group level and anonymized data in the publications that are planned to result from this study.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No