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

Phase 3

Recruiting

• Conditions: Diabetes; Metformin; Bariatric Surgery
• Interventions: Drug: Metformin; Other: Standard Care; Dietary Supplement: Standardized meal

• Registration Number: NCT04581447
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2020-09-28
• Study First Submitted QC: 2020-10-05
• Study First Posted: 2020-10-09
• Study Start: 2021-01-07
• Status Verified: 2023-06
• Last Update Submitted: 2023-06-07
• Last Update Posted: 2023-06-08
• Primary Completion: 2026-07
• Study Completion: 2026-11

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 126

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Metformin + Standard care	Metformin	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.
Metformin + Standard care	Standard Care	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.
Metformin + Standard care	Standardized meal	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.
Standard Care	Standard Care	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.
Standard Care	Standardized meal	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.

Primary Outcome Measures

Name	Time	Method
Proportion of patients with partial or complete T2D remission criteria	3 years	* 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).

Secondary Outcome Measures

Name	Time	Method
Proportion of patients with strict complete T2D remission criteria	3 years
Percentage of weight and BMI change	1, 2 and 3 years
Level of blood calcium	1, 2 and 3 years	Level of nutritional parameters associated with BS
Level of blood vitamin D	1, 2 and 3 years	Level of nutritional parameters associated with BS
Proportion of adverse effects in the intervention group compared to standard care	3 years
Number of pills taken per patient	1, 2 and 3 years	Adherence level assessment in the intervention group. Compliant patients are defined as taking at least 80% of assigned study pills in the intervention group.
Level of plasmatic metformin	1, 2 and 3 years	Adherence level assessment in the intervention group.
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	1, 2 and 3 years	assessed by EuroQol 5 Dimensions (EQ5D) auto-questionnaire
Proportion of patients with partial or complete T2D remission criteria	1 and 2 years	* 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).
Level of blood iron	1, 2 and 3 years	Level of nutritional parameters associated with BS
Level of serum ferritin	1, 2 and 3 years	Level of nutritional parameters associated with BS
Level of blood vitamin B1	1, 2 and 3 years	Level of nutritional parameters associated with BS
Fasting glycemia	1, 2 and 3 years	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).
Level of blood HDL cholesterol	1, 2 and 3 years	Assessment of the level of cardio-metabolic parameters associated to T2D.
Transferrin saturation percentage	1, 2 and 3 years	Level of nutritional parameters associated with BS
Fasting insulinemia	1, 2 and 3 years	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).
Level of blood triglycerides	1, 2 and 3 years	Assessment of the level of cardio-metabolic parameters associated to T2D.
Level of blood albumin	1, 2 and 3 years	Level of nutritional parameters associated with BS
Blood pressure	1, 2 and 3 years	Systolic and diastolic blood pressure.
Level of blood hemoglobin	1, 2 and 3 years	Level of nutritional parameters associated with BS
Level of blood vitamin B9	1, 2 and 3 years	Level of nutritional parameters associated with BS
Level of blood vitamin B12	1, 2 and 3 years	Level of nutritional parameters associated with BS
Clinical outcome at the end of the study	3 years	assessed by 5-year-Advanced-Diabetes Remission (5y-Ad-DiaRem) score
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

Trial Locations

Locations (16)

CH de Saint-Denis - hôpital Delafontaire; 🇫🇷 Saint-Denis, France

CHU Amiens-Picardie - hôpital Nord; 🇫🇷 Amiens, France

AP-HP - hôpital Louis-Mourier; 🇫🇷 Colombes, France

Centre hospitalier intercommunal de Créteil; 🇫🇷 Créteil, France

AP-HP - hôpital Bichat-Claude Bernard; 🇫🇷 Paris, France

AP-HM - hôpital Nord; 🇫🇷 Marseille, France

AP-HP - hôpital Avicenne; 🇫🇷 Bobigny, France

CHU de Bordeaux - hôpital Haut-Lévêque; 🇫🇷 Bordeaux, France

CHU de Lille - hôpital Claude Huriez; 🇫🇷 Lille, France

AP-HM - hôpital de la Conception; 🇫🇷 Marseille, France

HCL - centre hospitalier Lyon-Sud; 🇫🇷 Pierre-Bénite, France

AP-HP - hôpital européen Georges-Pompidou; 🇫🇷 Paris, France

CHU de Toulouse - hôpital Larrey; 🇫🇷 Toulouse, France

Institut Mutualiste Montsouris; 🇫🇷 Paris, France

AP-HP - hôpital Ambroise-Paré; 🇫🇷 Boulogne-Billancourt, France

AP-HP - hôpital de la Pitié-Salpêtrière; 🇫🇷 Paris, France