Clinical trial NCT04581447: Extending Time Without Diabetes After Bariatric Surgery: a Trial Comparing the Metformin Addition or Not to Standard Care
Official title: Extending Time Without Diabetes After Bariatric Surgery: a Randomized Controlled Trial Comparing the Metformin Addition or Not to Standard Care
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Diabetes
Bariatric Surgery
Metformin
Keywords: Diabetes
Bariatric Surgery
Sleeve gastrectomy
Gastric bypass
Metformin
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
First posted: 2020-10-09
Enrollment: 126
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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

Primary outcomes:
measure: Proportion of patients with partial or complete T2D remission criteria
timeFrame: 3 years
Secondary outcomes:
measure: Proportion of patients with partial or complete T2D remission criteria
timeFrame: 1 and 2 years
measure: Proportion of patients with strict complete T2D remission criteria
timeFrame: 3 years
measure: Percentage of weight and BMI change
timeFrame: 1, 2 and 3 years
measure: Fasting glycemia
timeFrame: 1, 2 and 3 years
measure: Fasting insulinemia
timeFrame: 1, 2 and 3 years
measure: Level of blood triglycerides
timeFrame: 1, 2 and 3 years
measure: Level of blood HDL cholesterol
timeFrame: 1, 2 and 3 years
measure: Blood pressure
timeFrame: 1, 2 and 3 years
measure: Level of blood albumin
timeFrame: 1, 2 and 3 years
measure: Level of blood hemoglobin
timeFrame: 1, 2 and 3 years
measure: Level of blood iron
timeFrame: 1, 2 and 3 years
measure: Level of serum ferritin
timeFrame: 1, 2 and 3 years
measure: Transferrin saturation percentage
timeFrame: 1, 2 and 3 years
measure: Level of blood calcium
timeFrame: 1, 2 and 3 years
measure: Level of blood vitamin D
timeFrame: 1, 2 and 3 years
measure: Level of blood vitamin B1
timeFrame: 1, 2 and 3 years
measure: Level of blood vitamin B9
timeFrame: 1, 2 and 3 years
measure: Level of blood vitamin B12
timeFrame: 1, 2 and 3 years
measure: Proportion of adverse effects in the intervention group compared to standard care
timeFrame: 3 years
measure: Number of pills taken per patient
timeFrame: 1, 2 and 3 years
measure: Level of plasmatic metformin
timeFrame: 1, 2 and 3 years
measure: Proportion of retinopathy events
timeFrame: 3 years
measure: Proportion of nephropathy events
timeFrame: 3 years
measure: Proportion of macroangiopathy events
timeFrame: 3 years
measure: Numbers and proportions of patients with quality of life changes
timeFrame: 1, 2 and 3 years
measure: Clinical outcome at the end of the study
timeFrame: 3 years
measure: Changes in fecal microbiota
timeFrame: 1 and 3 years
measure: Glycemia
timeFrame: 6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal
measure: Insulinemia
timeFrame: 6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal
measure: Level of glucagon
timeFrame: 6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal
measure: Level of GLP-1
timeFrame: 6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal
measure: Level of GLP-2
timeFrame: 6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal
measure: Level of GIP
timeFrame: 6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal
measure: Level of oxyntomodulin
timeFrame: 6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal
measure: Level of PYY
timeFrame: 6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal
measure: Level of ghrelin
timeFrame: 6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal
measure: Level of glicentin
timeFrame: 6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU Amiens-Picardie - hôpital Nord
city: Bobigny
country: France
facility: AP-HP - hôpital Avicenne
city: Bordeaux
country: France
facility: CHU de Bordeaux - hôpital Haut-Lévêque
city: Boulogne-Billancourt
country: France
facility: AP-HP - hôpital Ambroise-Paré
city: Colombes
country: France
facility: AP-HP - hôpital Louis-Mourier
city: Créteil
country: France
facility: Centre hospitalier intercommunal de Créteil
city: Lille
country: France
facility: CHU de Lille - hôpital Claude Huriez
city: Marseille
country: France
facility: AP-HM - hôpital de la Conception
city: Marseille
country: France
facility: AP-HM - hôpital Nord
city: Paris
country: France
facility: AP-HP - hôpital européen Georges-Pompidou
city: Paris
country: France
facility: AP-HP - hôpital Bichat-Claude Bernard
city: Paris
country: France
facility: AP-HP - hôpital de la Pitié-Salpêtrière
city: Paris
country: France
facility: Institut Mutualiste Montsouris
city: Pierre-Bénite
country: France
facility: HCL - centre hospitalier Lyon-Sud
city: Saint-Denis
country: France
facility: CH de Saint-Denis - hôpital Delafontaire
city: Toulouse
country: France
facility: CHU de Toulouse - hôpital Larrey
Study officials:
affiliation: claire.carette@aphp.fr
name: Claire CARETTE, MD
role: PRINCIPAL_INVESTIGATOR
References: