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

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Recruiting

CT.gov ID

NCT04581447

Collaborator

Ministry of Health, France (Other)

350

Enrollment

Locations

Arms

63.7

Anticipated Duration (Months)

21.9

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Bariatric Surgery Metformin	Drug: Metformin Other: Standard Care Dietary Supplement: Standardized meal	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

350 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

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

Actual Study Start Date :

Jan 7, 2021

Anticipated Primary Completion Date :

Jan 1, 2026

Anticipated Study Completion Date :

May 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Metformin + 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.	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)
Other: 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.	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)

Arm

Intervention/Treatment

Experimental: Metformin + 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.

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)

Other: 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.

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)

Outcome Measures

Primary Outcome Measures

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

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).
Proportion of patients with strict complete T2D remission criteria [3 years]
Percentage of weight and BMI change [1, 2 and 3 years]
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).
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 HDL cholesterol [1, 2 and 3 years]
Assessment of the level of cardio-metabolic parameters associated to T2D.
Blood pressure [1, 2 and 3 years]
Systolic and diastolic blood pressure.
Level of blood albumin [1, 2 and 3 years]
Level of nutritional parameters associated with BS
Level of blood hemoglobin [1, 2 and 3 years]
Level of nutritional parameters associated with BS
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
Transferrin saturation percentage [1, 2 and 3 years]
Level of nutritional parameters associated with BS
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
Level of blood vitamin B1 [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
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
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	CHU Amiens-Picardie - hôpital Nord	Amiens	France
2	AP-HP - hôpital Avicenne	Bobigny	France
3	CHU de Bordeaux - hôpital Haut-Lévêque	Bordeaux	France
4	AP-HP - hôpital Ambroise-Paré	Boulogne-Billancourt	France
5	AP-HP - hôpital Louis-Mourier	Colombes	France
6	Centre hospitalier intercommunal de Créteil	Créteil	France
7	CHU de Lille - hôpital Claude Huriez	Lille	France
8	AP-HM - hôpital de la Conception	Marseille	France
9	AP-HM - hôpital Nord	Marseille	France
10	AP-HP - hôpital européen Georges-Pompidou	Paris	France	75015
11	AP-HP - hôpital Bichat-Claude Bernard	Paris	France
12	AP-HP - hôpital de la Pitié-Salpêtrière	Paris	France
13	Institut Mutualiste Montsouris	Paris	France
14	HCL - centre hospitalier Lyon-Sud	Pierre-Bénite	France
15	CH de Saint-Denis - hôpital Delafontaire	Saint-Denis	France
16	CHU de Toulouse - hôpital Larrey	Toulouse	France