Comparative Study of Antiatherosclerotic Efficacy of Semaglutide, Dapagliflozin, and Metformin in Coronary Artery Disease with Prediabetes

The primary objective of this clinical study is to evaluate the **anti-atherosclerotic** efficacy of treatment with oral GLP-1 agonist (semaglutide) versus SGLT-2 inhibitor (dapagliflozin), compared to metformin, in patients with **coronary artery disease** (CAD) and **prediabetes**. The study aims to assess the effect of these treatments on coronary plaque progression or regression, as determined by contrast coronary computed tomography angiography (CCTA) over a 24-month observation period. This is clinically relevant as it may provide insights into the comparative effectiveness of these antidiabetic agents in managing coronary atherosclerosis in patients with CAD and prediabetes, potentially influencing treatment strategies and improving patient outcomes.

The clinical trial involves participants diagnosed with **coronary artery disease** and **prediabetes**, with an age range of 18 to 80 years. Both male and female subjects are included, and the study does not focus on a vulnerable population. The total number of participants is not provided by the sponsor. Participants were selected based on specific criteria, including a confirmed diagnosis of coronary artery disease, as evidenced by coronary atherosclerosis detected through coronary computed tomography angiography. Additionally, participants must have prediabetes, defined by specific fasting blood glucose levels or HbA1c percentages. All participants are required to have stable treatment and control of cardiovascular risk factors, including adherence to dietary and lifestyle management, for at least four weeks prior to the study. The trial does not include any vulnerable populations, and participants must demonstrate the capability and willingness to comply with all study requirements, including providing informed consent.

The clinical trial is designed as a **randomized**, open-label, multi-arm study to evaluate the anti-atherosclerotic efficacy of selected antidiabetic agents in patients with **coronary artery disease** and **prediabetes**. The trial will compare the effects of treatment with oral GLP-1 agonist (semaglutide) and SGLT-2 inhibitor (dapagliflozin) against metformin, alongside optimal diet and lifestyle modifications. The primary objective is to assess the impact of these treatments on coronary plaque progression or regression, as evaluated by coronary computed tomography angiography (CCTA) over a 24-month observation period. The trial is expected to commence recruitment in November 2024 and conclude by August 2029.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age (18-80 years), diagnosed coronary artery disease, and prediabetes. The inclusion visit will involve a core CT scan performed within three months prior to inclusion, ensuring stable treatment and control of cardiovascular risk factors. Follow-up visits will be scheduled periodically to monitor treatment effects, adherence, and any adverse events. The end-of-study visit will involve a final assessment of coronary plaque changes and other secondary endpoints, such as changes in inflammatory parameters, lipid levels, and body composition.

Participant involvement is anticipated to last for the full 24-month duration of the trial, with conditions for early termination including non-compliance with study requirements or the occurrence of significant adverse events. The trial will adhere to the terms of the marketing authorization, ensuring that the investigational medicinal products are administered according to the protocol, with minimal additional risk or burden to participants compared to standard clinical practice. The study will provide valuable insights into the comparative efficacy of these antidiabetic agents in managing coronary artery disease and prediabetes.

The clinical trial involves the administration of several **experimental medications** to evaluate their anti-atherosclerotic efficacy in patients with coronary artery disease and prediabetes. The primary experimental medication is **Rybelsus**, which contains the active substance **semaglutide**. Rybelsus is available in three different dosages: 3 mg, 7 mg, and 14 mg tablets. The pharmaceutical form is a tablet, and the route of administration is oral. The maximum daily dose for each respective formulation is 3 mg, 7 mg, and 14 mg, with a treatment period extending up to 24 months. The medication is manufactured by Novo Nordisk A/S and is not a paediatric formulation.

Another experimental medication used in the trial is **Forxiga**, which contains the active substance **dapagliflozin**. Forxiga is provided as a 10 mg film-coated tablet, administered orally. The maximum daily dose is 10 mg, and the treatment duration is also up to 24 months. This medication is produced by AstraZeneca AB and is classified as a chemical substance.

The trial also includes a **comparator treatment** with **Formetic**, which contains the active substance **metformin hydrochloride**. Formetic is available as a 500 mg film-coated tablet, with a maximum daily dose of 500 mg and a total maximum dose of 1000 mg. The administration route is oral, and the treatment period is up to 24 months. This medication is manufactured by Zakłady Farmaceutyczne Polpharma S.A. and is also classified as a chemical substance.

All medications are administered orally, and participant compliance is monitored throughout the study. The trial aims to compare the efficacy of these treatments in reducing coronary plaque progression or promoting regression, as assessed by coronary computed tomography angiography over the observation period.

The efficacy of the clinical trial will be assessed by evaluating the anti-atherosclerotic effects of the treatments on patients with coronary artery disease (CAD) and prediabetes. The primary endpoint is the impact of treatment on the progression or regression of coronary plaque, as assessed by coronary computed tomography angiography (CCTA) over a 24-month observation period. The primary outcome measures include the change in the volume of non-calcified atherosclerotic plaque, expressed as a percentage change, in patients treated with a GLP-1 analogue, **semaglutide**, and an SGLT-2 inhibitor, **dapagliflozin**, compared to routine treatment.

Secondary endpoints will further explore the effects of the tested drugs versus the control group on various aspects of coronary artery disease progression. These include changes in the volume of uncalcified atherosclerotic plaque, the conversion of non-calcified plaque into calcified plaque, and the dynamics of high-risk atherosclerotic lesions. Additional assessments will include changes in body composition, inflammatory parameters, lipid levels, glycated hemoglobin (HbA1c), blood pressure, smoking status, physical activity compliance, dietary compliance, and the onset of diabetes and heart failure. The trial will also evaluate the number of unplanned hospitalizations, major cardiovascular events, and changes in oxidative stress markers. These efficacy parameters will be measured and analyzed using validated scales and laboratory tests at specified timepoints throughout the study duration.