Evaluation of Dapagliflozin and Oral Semaglutide in Phenotyping and Personalized Treatment of Type 2 Diabetes Based on Insulin Resistance and Secretion Deficit

The primary objective of this study is to assess the responses to different glucose-lowering treatments, specifically **dapagliflozin** versus oral **semaglutide**, in patients with type 2 diabetes (T2D). These patients are categorized into two groups based on their prevalent insulin resistance (IR) or insulin secretion deficit (ISD). The clinical relevance of this objective lies in understanding the differential responses to therapy, which will be monitored using a series of non-canonical biomarkers such as adiponectin, irisin, and serpin B1, as well as canonical biomarkers including HbA1c, glucagon, GLP-1, GIP, insulin, and proinflammatory mediators. This evaluation is crucial for optimizing treatment strategies tailored to the specific pathophysiological profiles of T2D patients.

Secondary objectives include identifying a series of non-canonical or canonical biomarkers, or other metabolites potentially detected in metabo-lipidomic analysis, that could represent a "signature" of the IR or ISD phenotype. This identification aims to implement personalized treatment for certain phenotypes of T2D patients treated with GLP-1 receptor agonists (GLP-1RA) or sodium-glucose co-transporter 2 inhibitors (SGLT-2is).

The clinical trial involves participants diagnosed with **type 2 diabetes**, with an age range of 20 to 70 years, including both male and female subjects. The study population is characterized by individuals who have been on stable metformin therapy for at least six months and exhibit suboptimal glycemic control, indicated by an HbA1c level between 7.5% and 9%. Participants are required to have a fasting C-peptide level greater than 1 ng/mL (0.33 nmol/L) and must be capable of taking oral medications. Women of childbearing potential are included, provided they have a negative pregnancy test at baseline and agree to use adequate contraception. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the differential responses to glucose-lowering treatments in patients with **type 2 diabetes**. This is a phase IV, multi-center, prospective, non-blind randomized trial. The study will compare the effects of **dapagliflozin**, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and **semaglutide**, a glucagon-like peptide-1 (GLP-1) analogue, in patients categorized based on their insulin resistance or insulin secretion deficit. The trial will utilize both canonical and non-canonical biomarkers to monitor treatment responses, including glycated hemoglobin (HbA1c), glucagon, GLP-1, and other metabolites detected through metabo-lipidomic analysis.

The trial is expected to commence recruitment in November 2024 and conclude by November 2026. Participants will be involved in the study for a maximum treatment period of up to 24 weeks, depending on the specific treatment arm. The study will include an initial screening visit to confirm eligibility based on criteria such as age, sex, stable metformin therapy, and glycemic control levels. Following the screening, participants will be randomized to receive either dapagliflozin or semaglutide, with follow-up visits scheduled to assess treatment efficacy and safety. The end-of-study visit will evaluate the primary endpoint, which is the differential effect of the treatments on metabolic compensation and beta-cell function, as measured by HbA1c levels.

Participants are expected to comply with the study protocol, including attending all scheduled visits and adhering to the prescribed treatment regimen. Conditions that may lead to early termination from the study include non-compliance with the protocol, adverse events, or withdrawal of consent. The trial aims to provide insights into the personalized treatment of type 2 diabetes by identifying biomarkers that can guide therapeutic decisions.

The clinical trial involves the administration of **Dapagliflozin**, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, which is utilized in the management of type 2 diabetes. The pharmaceutical form of Dapagliflozin is a film-coated tablet, and it is administered orally. The maximum daily dose is 10 mg, with a total treatment period of up to 6 months. The medication is of chemical origin and is not formulated for pediatric use. Participant compliance with the dosing schedule will be monitored throughout the trial.

**Semaglutide** is another experimental medication used in this trial, classified as a Glucagon-like peptide-1 (GLP-1) analogue. It is available in tablet form and is also administered orally. Two different dosing regimens are being evaluated: one with a maximum daily dose of 3 mg over a 4-week period, and another with a maximum daily dose of 7 mg over a 22-week period. Semaglutide is of protein origin and is not intended for pediatric use. Compliance with the dosing schedule will be closely monitored to ensure adherence.

In addition to the experimental treatments, **Insulin Glargine** is used as a comparator treatment. It is a long-acting insulin analogue administered as a solution for subcutaneous injection. The maximum daily dose is 1 IU/kg, with a treatment duration of up to 24 weeks. Insulin Glargine is of protein origin and is not formulated for pediatric use. Participant adherence to the administration schedule will be monitored to ensure accurate dosing.

Efficacy in this clinical trial will be assessed by evaluating the differential effects of treatment with **semaglutide** versus **dapagliflozin** on metabolic compensation and beta-cell function, specifically measured through glycated hemoglobin (**HbA1c**). The primary endpoint focuses on the changes in **HbA1c** levels, which serve as a key indicator of metabolic control in patients with type 2 diabetes (T2D). Secondary endpoints include the ability of biomarkers to provide a signature for patient phenotyping post-treatment and to guide the choice between **dapagliflozin** or **semaglutide** based on distinct diabetic patient phenotypes.

The trial will monitor responses using a series of non-canonical biomarkers such as adiponectin, irisin, and serpin B1, alongside canonical biomarkers including **HbA1c**, glucagon, GLP-1, GIP, insulin, and proinflammatory mediators. These biomarkers will be assessed to determine their potential in offering a phenotypic signature and guiding treatment decisions. The efficacy parameters will be collected and analyzed at specified intervals throughout the trial duration, ensuring a comprehensive evaluation of the treatment effects on the targeted patient population.