Extending Time Without Diabetes After Bariatric Surgery: a Trial Comparing the Metformin Addition or Not to Standard Care

Study Overview
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Brief Summary
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This study is a randomized trial that evaluates the effect of metformin addition or not to standard care on the duration of diabetes remission after bariatric surgery.

Detailed Description
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In addition to significant weight loss, several randomized control trials (RCTs) have demonstrated that bariatric surgery can reverse or at least improve type 2 diabetes (T2D). Despite the variability in study design and patient characteristics of these RCTs, there is a consistent favorable effect of surgery compared to medical treatment for weight loss, change in HbA1c, reduction in diabetes medications, remission of metabolic syndrome and improvement in quality of life. Diabetes remission rate is estimated from 15 to 45 % according to the 4 available RCT including the most used surgery (Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG)) with at least three to five years of follow-up. These results mean that more than half of patients with type 2 diabetes are still or newly diagnosed with diabetic after surgery and that extending time of diabetes remission after bariatric surgery is of major concern. No RCT has explored yet an intervention to extend diabetes remission. Apart from bariatric surgery, metformin is unequivocally recommended to treat both diabetes and pre-diabetes along with lifestyle interventions. Results of the Diabetes Prevention Program trial showed that metformin reduces diabetes incidence by 31% in obese patients with pre-diabetes. We hypothesized that metformin might extend the duration of diabetes remission after bariatric surgery. The study is a randomized, controlled, open-labeled, multicenter trial. Patients fulfilling the inclusion criteria and without any of the exclusion criteria will be randomized. Patients will receive: Standardized care plus metformin treatment if randomized in the experimental group given for 3 years Standardized care alone if randomized in the reference group Primary objective is to demonstrate that metformin increases the proportion of patients with T2D remission compared to standard care among ex-T2D patients operated of BS, after a 3-year period of treatment. Secondary objectives are: To assess the proportion of patients with T2D partial or complete remission with metformin compared to standard care in ex-T2D patients operated of BS, after 1 and 2 years of treatment. To assess body weight and metabolic parameters in metformin group versus standard care. To assess tolerance, nutritional status and adherence to metformin in intervention group versus standard care. To assess micro and macroangiopathy at 3 years. To assess quality of life changes from baseline at 1, 2 and 3 years. To assess the accuracy of long term prediction score (i.e. prolonged remission assessed at the end of the study with the Ad-DiaRem score) To explore gut contribution to metformin metabolic effect by: (i) gut microbiota differences (diversity, composition and function) between metformin treated and non-treated individuals and (ii) measurements of metformin-induced enterohormones secretion Patients are followed up every 6 months during 3 years in both arms. If diabetes is diagnosed during the follow-up (HbA1c > 6.5 %), the primary endpoint of the study is obtained meaning end of diabetes remission but patients will be still followed up to the end of protocol to monitor the secondary endpoints. When remission is over, the care defined by the protocol (ie metformin + standardized care or standardized care alone) should be stopped. In both groups, when remission is over, management of the disease has to be adapted according to physician's and patient's preference whatever the arm of randomization.

Official Title
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Extending Time Without Diabetes After Bariatric Surgery: a Randomized Controlled Trial Comparing the Metformin Addition or Not to Standard Care

Conditions
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Diabetes, Bariatric Surgery, Metformin

Intervention / Treatment
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* Drug: Metformin
* Other: Standard Care
* Dietary Supplement: Standardized meal


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults 18-70 years old Having undergone gastric bypass or sleeve gastrectomy 12 to 36 +/-3 months before inclusion ex-T2D treated with at least one anti-diabetic drug before bariatric surgery or HbA1c ≥ 6.5 % before bariatric surgery HbA1C < 6.5 % at inclusion with no anti-hyperglycemic medications for the last three months Written consent Exclusion Criteria: Known type 1 diabetes Pregnancy and breastfeeding Estimated glomerular filtration rate<44 ml/min (MDRD) Known intolerance to metformin Known contraindication to metformin: Acute metabolic acidosis Acute affection which could lead to renal deterioration (ex: dehydration, serious infection, shock, intravascular administration of iodinated contrast agent within the last 48 hours) Acute or chronic disease which could lead to a tissue hypoxia (ex : severe cardiac insufficiency, severe respiratory insufficiency, myocardial infarction within the last 3 months, shock) Hepatocellular insufficiency Prothrombin ratio ≤ 50% SGOT or SGPT levels ≥ 10 times the upper limits of the normal range Alcohol use disorder Medications and medical conditions likely to confound the assessment of diabetes: glucocorticoids treatment renal graft Cushing's syndrome acromegaly fasting plasma triglyceride > 600 mg/dl despite treatment Patient under legal protection

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin + Standard care<br>The pharmacological treatment (Metformin) will start at dose of 850 mg once daily and, at one month, increased to 850 mg twice daily. The dosage will be adjusted if necessary because of gastrointestinal symptoms and information on dose change during follow-up will be collected Adherence to study medications will be assessed by pills count and plasmatic dosage (Metformin group). All participants will receive standardized lifestyle recommendations regularly during all the time of the study Lifestyle recommendations will be provided by a nutritionist/diabetologist every 6 months at each study visit and reinforced by dedicated consultations with a dietician and a physical activity coach as usually performed in each center. This follow-up will be standardized for each center and applied equally to patients of both groups. Ancillary study measuring metformin-induced enterohormones secretion will be performed on a subgroup of 30 patients randomized in this arm. | Drug: Metformin<br>* Metformin will start at dose of 850 mg once daily and, at one month increased to 850 mg twice daily<br>Other: Standard Care<br>* Standard Care<br>Dietary Supplement: Standardized meal<br>* Measurements of metformin-induced enterohormones secretion will be done after standardized meal test in a subgroup of patients (ancillary study)<br>|
| Other: Standard Care<br>All participants will receive standardized lifestyle recommendations regularly during all the time of the study Lifestyle recommendations will be provided by a nutritionist/diabetologist every 6 months at each study visit and reinforced by dedicated consultations with a dietician and a physical activity coach as usually performed in each center. This follow-up will be standardized for each center and applied equally to patients of both groups. Ancillary study measuring metformin-induced enterohormones secretion will be performed on a subgroup of 30 patients randomized in this arm. | Other: Standard Care<br>* Standard Care<br>Dietary Supplement: Standardized meal<br>* Measurements of metformin-induced enterohormones secretion will be done after standardized meal test in a subgroup of patients (ancillary study)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with partial or complete T2D remission criteria | Complete remission: HbA1c<5.7% and no anti-diabetic medications (except metformin in the experimental group). Partial remission: defined as prediabetes level of glycaemia i.e. HbA1c<6.5% and no anti-diabetic medications (except metformin in the experimental group). | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with partial or complete T2D remission criteria | Complete remission: HbA1c<5.7% and no anti-diabetic medications (except metformin in the experimental group). Partial remission: defined as prediabetes level of glycaemia i.e. HbA1c<6.5% and no anti-diabetic medications (except metformin in the experimental group). | 1 and 2 years | 
| Proportion of patients with strict complete T2D remission criteria |  | 3 years | 
| Percentage of weight and BMI change |  | 1, 2 and 3 years | 
| Fasting glycemia | Assessment of the level of cardio-metabolic parameters associated to T2D. Fasting glycemia and insulinemia will be combined to report HOMA-IR (homeostatic model assessment - insulin resistance). | 1, 2 and 3 years | 
| Fasting insulinemia | Assessment of the level of cardio-metabolic parameters associated to T2D. Fasting glycemia and insulinemia will be combined to report HOMA-IR (homeostatic model assessment - insulin resistance). | 1, 2 and 3 years | 
| Level of blood triglycerides | Assessment of the level of cardio-metabolic parameters associated to T2D. | 1, 2 and 3 years | 
| Level of blood HDL cholesterol | Assessment of the level of cardio-metabolic parameters associated to T2D. | 1, 2 and 3 years | 
| Blood pressure | Systolic and diastolic blood pressure. | 1, 2 and 3 years | 
| Level of blood albumin | Level of nutritional parameters associated with BS | 1, 2 and 3 years | 
| Level of blood hemoglobin | Level of nutritional parameters associated with BS | 1, 2 and 3 years | 
| Level of blood iron | Level of nutritional parameters associated with BS | 1, 2 and 3 years | 
| Level of serum ferritin | Level of nutritional parameters associated with BS | 1, 2 and 3 years | 
| Transferrin saturation percentage | Level of nutritional parameters associated with BS | 1, 2 and 3 years | 
| Level of blood calcium | Level of nutritional parameters associated with BS | 1, 2 and 3 years | 
| Level of blood vitamin D | Level of nutritional parameters associated with BS | 1, 2 and 3 years | 
| Level of blood vitamin B1 | Level of nutritional parameters associated with BS | 1, 2 and 3 years | 
| Level of blood vitamin B9 | Level of nutritional parameters associated with BS | 1, 2 and 3 years | 
| Level of blood vitamin B12 | Level of nutritional parameters associated with BS | 1, 2 and 3 years | 
| Proportion of adverse effects in the intervention group compared to standard care |  | 3 years | 
| Number of pills taken per patient | Adherence level assessment in the intervention group. Compliant patients are defined as taking at least 80% of assigned study pills in the intervention group. | 1, 2 and 3 years | 
| Level of plasmatic metformin | Adherence level assessment in the intervention group. | 1, 2 and 3 years | 
| Proportion of retinopathy events |  | 3 years | 
| Proportion of nephropathy events |  | 3 years | 
| Proportion of macroangiopathy events |  | 3 years | 
| Numbers and proportions of patients with quality of life changes | assessed by EuroQol 5 Dimensions (EQ5D) auto-questionnaire | 1, 2 and 3 years | 
| Clinical outcome at the end of the study | assessed by 5-year-Advanced-Diabetes Remission (5y-Ad-DiaRem) score | 3 years | 
| Changes in fecal microbiota |  | 1 and 3 years | 
| Glycemia |  | 6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal | 
| Insulinemia |  | 6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal | 
| Level of glucagon |  | 6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal | 
| Level of GLP-1 |  | 6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal | 
| Level of GLP-2 |  | 6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal | 
| Level of GIP |  | 6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal | 
| Level of oxyntomodulin |  | 6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal | 
| Level of PYY |  | 6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal | 
| Level of ghrelin |  | 6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal | 
| Level of glicentin |  | 6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Bariatric Surgery, Sleeve gastrectomy, Gastric bypass, Metformin