Randomized Controlled Trial Evaluating Metformin Versus Standard Care for Prolonging Type 2 Diabetes Remission Post-Bariatric Surgery

The primary objective of this study is to demonstrate that **metformin** increases the proportion of patients achieving remission of Type 2 Diabetes (T2D) compared to standard care among individuals who have undergone bariatric surgery, over a 3-year treatment period. This is clinically relevant as it evaluates the potential of metformin to extend the duration of diabetes remission, which could significantly impact long-term management and quality of life for patients post-surgery.

Secondary objectives include:

• Assessing the proportion of patients with partial or complete T2D remission with metformin compared to standard care after 1 and 2 years of treatment.
• Evaluating body weight and metabolic parameters in the metformin group versus standard care.
• Assessing tolerance, nutritional status, and adherence to metformin in the intervention group versus standard care.
• Evaluating micro and macroangiopathy at 3 years.
• Assessing quality of life changes from baseline at 1, 2, and 3 years.
• Evaluating the accuracy of a long-term prediction score for prolonged remission using the Ad-DiaRem score.
• Exploring differences in gut microbiota diversity, composition, and function between metformin-treated and non-treated individuals.

The clinical trial involves participants who have experienced **Type 2 Diabetes** complete remission following bariatric surgery while under antidiabetic medication. The study population comprises adults aged 18 to 70 years, including both male and female subjects. Participants have undergone either gastric bypass or sleeve gastrectomy between 12 to 36 months prior to inclusion in the study. They are ex-Type 2 Diabetes patients who were treated with at least one antidiabetic drug before their bariatric surgery or had an HbA1c level of 6.5% or higher before the surgery. At the time of inclusion, participants must have an HbA1c level below 6.5% without the use of anti-hyperglycemic medications for the preceding three months. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Written consent is a requirement for participation. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized**, open-label, multisite, two-arm study designed to evaluate the efficacy of **metformin** in extending the remission period of **Type 2 Diabetes** (T2D) following bariatric surgery. The trial aims to demonstrate that metformin increases the proportion of patients achieving T2D remission compared to standard care over a three-year treatment period. The study will involve adult participants aged 18 to 70 who have undergone gastric bypass or sleeve gastrectomy 12 to 36 months prior to inclusion and have achieved T2D remission without anti-hyperglycemic medications for the last three months. The primary endpoint is the proportion of patients with partial or complete T2D remission at three years, assessed using criteria from the American Diabetes Association guidelines.

The trial will commence with a screening visit to confirm eligibility based on the inclusion criteria, including HbA1C levels and previous treatment history. Participants will be randomly assigned to either the metformin group or the standard care group. The trial will include follow-up visits at one, two, and three years to assess primary and secondary endpoints, such as changes in weight, BMI, cardio-metabolic parameters, and quality of life. The end-of-study visit will occur at the three-year mark, where final assessments will be conducted. The expected duration of participant involvement is approximately three years, with conditions for early termination including withdrawal of consent or adverse events.

Secondary endpoints will evaluate the proportion of patients with T2D remission at one and two years, changes in nutritional parameters, and the incidence of adverse drug reactions. Adherence to the metformin regimen will be monitored through pill counts and plasma dosage measurements. The trial will also assess the impact on retinopathy, nephropathy, macroangiopathy, and changes in fecal microbiota. The study is expected to conclude by May 2028, with recruitment having started in January 2021. Participants will be required to provide written consent prior to enrollment, and the trial will adhere to ethical standards and regulatory requirements throughout its duration.

The clinical trial involves the administration of **Metformin**, a pharmaceutical agent classified under the ATC code A10BA02. Metformin is utilized in this study to evaluate its efficacy in increasing the proportion of patients achieving remission from type 2 diabetes (T2D) following bariatric surgery. The pharmaceutical form of Metformin is designated as PHF00245MIG, and it is administered orally. The maximum daily dose of Metformin is 1700 mg, with a total maximum dose of 1836 g over the course of the treatment period. The treatment duration is set for a maximum of 36 months. Metformin is not formulated specifically for pediatric use in this trial.

In addition to the experimental treatment with Metformin, the study includes a standard-of-care therapy as a comparator. This standard care serves as the control group to assess the effectiveness of Metformin in achieving T2D remission. The trial is designed to compare the outcomes of patients receiving Metformin in conjunction with standard care against those receiving standard care alone. Compliance with the dosing schedule and administration is monitored throughout the study to ensure adherence to the protocol and to accurately assess the treatment's impact on the participants.

Efficacy in the clinical trial titled "DIABOUT - Extending time without diabetes after bariatric surgery: a randomized controlled trial comparing the metformin addition or not to standard care" will be assessed primarily by evaluating the **proportion of patients with partial or complete Type 2 Diabetes (T2D) remission** at three years post-treatment. The criteria for diabetes remission will follow the 2012 American Diabetes Association guidelines, where complete remission is defined as HbA1c < 5.7% with no anti-diabetic medication (except metformin in the experimental group), and partial remission as HbA1c < 6.5% with no anti-diabetic medication (except metformin in the experimental group).

Secondary endpoints include the proportion of patients achieving T2D remission at one and two years, the percentage of weight and BMI change at one, two, and three years compared to baseline, and the levels of cardio-metabolic parameters such as fasting glycaemia, insulinemia, HOMA-IR, triglycerides, HDL cholesterol, and blood pressure at the same intervals. Nutritional parameters associated with bariatric surgery, including albumin, hemoglobin, iron, serum ferritin, transferrin saturation, calcium, and vitamins D, B1, B9, and B12, will also be measured. Additional assessments will include the proportion of adverse drug reactions, adherence levels in the intervention group, and the number and level of retinopathy, nephropathy, and macroangiopathy events at three years. Quality of life changes will be evaluated using the EQ5D auto-questionnaire, and the 5y-Ad-Diarem score will be calculated to assess clinical outcomes. Changes in fecal microbiota diversity, composition, and function will be analyzed from baseline at one and three years.