People with newly diagnosed type 2 diabetes treated with metformin that have not reached their HbA1c target (42-64 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.

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.

Inclusion Criteria:

• Signed informed consent
• BMI 25 kg/m2 or higher
• HbA1c 42 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

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.