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

Diabetes Clinical Trial

— DiabOUT  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04581447
• Other study ID #: P170901J
• Secondary ID: 2019-000312-28PH
• Status: Recruiting
• Phase: Phase 3
• Start date: January 7, 2021
• Est. completion date: November 2026

Study information

• Verified date: June 2023
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Aurélie GUIMFACK
• Email: aurelie.guimfack[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 126
• Est. completion date: November 2026
• Est. primary completion date: July 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Bariatric Surgery
• Diabetes
• Diabetes Mellitus
• Metformin

Intervention

Drug:
• Metformin
Metformin will start at dose of 850 mg once daily and, at one month increased to 850 mg twice daily

Other:
• Standard Care
Standard Care

Dietary Supplement:
• Standardized meal
Measurements of metformin-induced enterohormones secretion will be done after standardized meal test in a subgroup of patients (ancillary study)

Locations

Country	Name	City	State
France	CHU Amiens-Picardie - hôpital Nord	Amiens
France	AP-HP - hôpital Avicenne	Bobigny
France	CHU de Bordeaux - hôpital Haut-Lévêque	Bordeaux
France	AP-HP - hôpital Ambroise-Paré	Boulogne-Billancourt
France	AP-HP - hôpital Louis-Mourier	Colombes
France	Centre hospitalier intercommunal de Créteil	Créteil
France	CHU de Lille - hôpital Claude Huriez	Lille
France	AP-HM - hôpital de la Conception	Marseille
France	AP-HM - hôpital Nord	Marseille
France	AP-HP - hôpital Bichat-Claude Bernard	Paris
France	AP-HP - hôpital de la Pitié-Salpêtrière	Paris
France	AP-HP - hôpital européen Georges-Pompidou	Paris
France	Institut Mutualiste Montsouris	Paris
France	HCL - centre hospitalier Lyon-Sud	Pierre-Bénite
France	CH de Saint-Denis - hôpital Delafontaire	Saint-Denis
France	CHU de Toulouse - hôpital Larrey	Toulouse

Sponsors (2)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	Ministry of Health, France

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Proportion of patients with strict complete T2D remission criteria		3 years
Secondary	Percentage of weight and BMI change		1, 2 and 3 years
Secondary	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
Secondary	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
Secondary	Level of blood triglycerides	Assessment of the level of cardio-metabolic parameters associated to T2D.	1, 2 and 3 years
Secondary	Level of blood HDL cholesterol	Assessment of the level of cardio-metabolic parameters associated to T2D.	1, 2 and 3 years
Secondary	Blood pressure	Systolic and diastolic blood pressure.	1, 2 and 3 years
Secondary	Level of blood albumin	Level of nutritional parameters associated with BS	1, 2 and 3 years
Secondary	Level of blood hemoglobin	Level of nutritional parameters associated with BS	1, 2 and 3 years
Secondary	Level of blood iron	Level of nutritional parameters associated with BS	1, 2 and 3 years
Secondary	Level of serum ferritin	Level of nutritional parameters associated with BS	1, 2 and 3 years
Secondary	Transferrin saturation percentage	Level of nutritional parameters associated with BS	1, 2 and 3 years
Secondary	Level of blood calcium	Level of nutritional parameters associated with BS	1, 2 and 3 years
Secondary	Level of blood vitamin D	Level of nutritional parameters associated with BS	1, 2 and 3 years
Secondary	Level of blood vitamin B1	Level of nutritional parameters associated with BS	1, 2 and 3 years
Secondary	Level of blood vitamin B9	Level of nutritional parameters associated with BS	1, 2 and 3 years
Secondary	Level of blood vitamin B12	Level of nutritional parameters associated with BS	1, 2 and 3 years
Secondary	Proportion of adverse effects in the intervention group compared to standard care		3 years
Secondary	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
Secondary	Level of plasmatic metformin	Adherence level assessment in the intervention group.	1, 2 and 3 years
Secondary	Proportion of retinopathy events		3 years
Secondary	Proportion of nephropathy events		3 years
Secondary	Proportion of macroangiopathy events		3 years
Secondary	Numbers and proportions of patients with quality of life changes	assessed by EuroQol 5 Dimensions (EQ5D) auto-questionnaire	1, 2 and 3 years
Secondary	Clinical outcome at the end of the study	assessed by 5-year-Advanced-Diabetes Remission (5y-Ad-DiaRem) score	3 years
Secondary	Changes in fecal microbiota		1 and 3 years
Secondary	Glycemia		6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal
Secondary	Insulinemia		6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal
Secondary	Level of glucagon		6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal
Secondary	Level of GLP-1		6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal
Secondary	Level of GLP-2		6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal
Secondary	Level of GIP		6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal
Secondary	Level of oxyntomodulin		6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal
Secondary	Level of PYY		6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal
Secondary	Level of ghrelin		6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal
Secondary	Level of glicentin		6 months or 12 months; under fasting condition then 30 and 90 min after a standardized meal