Insulin resistance in type 2 diabetes: evaluating the pathogenic mechanisms of insulin resistance in the myocardium and the effects of the treatments with GLP-1RA and SGLT2i

The primary objective is to determine whether myocardial insulin resistance affects cardiac function and coronary flow in patients with type 2 diabetes mellitus exhibiting a myocardial insulin resistance phenotype, thereby establishing its role as a risk factor for cardiovascular events and diabetic cardiomyopathy. This evaluation will be performed using 18F-FDG PET/CT and 99mTc-Tetrofosmin SPECT imaging modalities. The clinical relevance lies in identifying myocardial insulin resistance as a potential pathogenic mechanism contributing to cardiac complications in type 2 diabetes mellitus, which may inform risk stratification and therapeutic strategies.

The secondary objectives include:

• Identification of biomarkers through metabolomic and lipidomic analyses that correlate with myocardial ischemia-reperfusion injury, cardiac function, and coronary flow, with the aim of enabling personalized management of patients with type 2 diabetes mellitus.

• Evaluation of the effects of semaglutide, a GLP-1 receptor agonist, and dapagliflozin, an SGLT2 inhibitor, on myocardial insulin resistance.

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population included both male and female subjects across adult and elderly age ranges. Participants were individuals diagnosed with Type 2 diabetes presenting with a myocardial insulin resistance phenotype. Key selection criteria included a body mass index (BMI) of approximately 30 kg/m², HbA1c levels between 7-9%, and adherence to a non-smoking and non-alcohol consuming lifestyle. The trial focused on patients with diabetic cardiomyopathy risk factors to investigate the relationship between myocardial insulin resistance and cardiac function through advanced imaging techniques.

This clinical trial investigates insulin resistance in the myocardium of patients with type 2 diabetes and evaluates the pathogenic mechanisms underlying this condition, as well as the effects of treatment with GLP-1 receptor agonists and SGLT2 inhibitors. The study is designed as a low intervention clinical trial and aims to determine whether myocardial insulin resistance affects cardiac function and coronary flow, thereby representing a risk factor for cardiovascular events and diabetic cardiomyopathy in patients with type 2 diabetes exhibiting a myocardial insulin resistance phenotype. The trial utilizes 18F-FDG PET/CT and 99mTc-Tetrofosmin SPECT imaging modalities to assess myocardial insulin resistance and related cardiovascular parameters.

The investigational medicinal products include semaglutide administered as a solution for injection in pre-filled pen via the subcutaneous route, with a maximum daily dose of 375,000 micrograms and a maximum total dose of 6 milligrams over the treatment period, and dapagliflozin propanediol administered as film-coated tablets via the oral route, with a maximum daily dose of 10 milligrams and a maximum total dose of 1,120 milligrams over the treatment period. Semaglutide serves as the test product while dapagliflozin functions as the comparator. The maximum treatment period for both products is 16 weeks.

The primary endpoint of the study is myocardium insulin resistance, while secondary endpoints include coronary flow and heart function. Principal inclusion criteria require participants to have a body mass index around 30 kg/m², confirmed type 2 diabetes, non-smoking and non-alcohol consuming status, and HbA1c levels between 7% and 9%. The trial is scheduled to commence recruitment in September 2025 and is estimated to conclude in July 2027.

The experimental medication **Ozempic** contains **semaglutide** as the active substance, which is a protein-based compound. The product is formulated as a **solution for injection** supplied in a **pre-filled pen** with a strength of 1 mg. The medication is administered via the **subcutaneous route**. The maximum daily dose is 375,000 micrograms (equivalent to 0.375 mg), with a maximum total dose of 6 mg over the treatment period. The maximum treatment period is 16 weeks. This product holds marketing authorization and is manufactured by Novo Nordisk A/S. The **ATC code** for semaglutide is A10BJ06, classifying it as a **glucagon-like peptide-1 receptor agonist (GLP-1RA)**.

The comparator treatment used in this study is **Dapagliflozin**, formulated as **film-coated tablets** with a strength of 10 mg. The active substance is **dapagliflozin propanediol**, which is a chemical compound. The medication is administered via the **oral route**. The maximum daily dose is 10 mg, with a maximum total dose of 1,120 mg over the treatment period. The maximum treatment period is 16 weeks. This product holds marketing authorization and is manufactured by Cipla (EU) Limited. The **ATC code** for dapagliflozin is A10BK01, classifying it as a **sodium-glucose co-transporter 2 inhibitor (SGLT2i)**.

Both medications are authorized products with established marketing approval status. Neither product is formulated as a **paediatric formulation**. The study design incorporates these two distinct pharmacological agents to evaluate their effects on **myocardial insulin resistance** in patients with **type 2 diabetes**. Participant compliance monitoring and adherence to the specified dosing schedules will be essential components of the trial conduct to ensure accurate assessment of treatment effects on cardiac function and coronary flow.

The primary endpoint for efficacy assessment in this clinical trial is **myocardium insulin resistance**. This parameter will be evaluated to determine whether myocardial insulin resistance affects cardiac function and coronary flow in patients with **type 2 diabetes**. The assessment will utilize 18F-FDG PET/CT and 99mTc-Tetrofosmin SPECT imaging techniques to measure myocardial insulin resistance and its impact on cardiovascular outcomes.

Secondary endpoints include **coronary flow** and **heart function**. These parameters will be assessed to further evaluate the cardiovascular effects of myocardial insulin resistance in the study population. The treatment period is planned for 16 weeks, during which the effects of **GLP-1 receptor agonist** (semaglutide) and **SGLT2 inhibitor** (dapagliflozin) will be evaluated on the specified efficacy endpoints.