Adipose Tissue Heterogeneity and Its Link to Type 2 Diabetes

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Pioglitazone 45 mg
* Drug: Empagliflozin 25 MG
* Drug: Semaglutide 7 MG


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants are recruited to either of three groups where they receive (in addition to metformin) any of the three study drugs.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pioglitazone<br>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<br>* Starts with 45 mg<br>|
| Experimental: Empagliflozin<br>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<br>* Starts with 25 mg<br>|
| Experimental: Semaglutide<br>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<br>* Starts with 3 mg daily for the first 2 weeks<br>|

What is the study measuring?
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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 |