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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Diabetes; Bariatric Surgery; Metformin
• Intervention / Treatment: Other: Standard Care; Drug: Metformin; Dietary supplement: Standardized meal

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 Type: Interventional
• Enrollment (Estimated): 126
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Yvann Frigout; Email: yvann.frigout@aphp.fr
• Study Contact Backup: Name: Aurélie GUIMFACK; Email: aurelie.guimfack@aphp.fr

Study Locations

• France
  • Amiens, France
    • Recruiting
    • CHU AMIENS-PICARDIE - Hôpital Nord
    • Contact: Jean-Daniel Lalau, MD; Email: lalau.jean-daniel@chu-amiens.fr
  • Bobigny, France
    • Withdrawn
    • AP-HP - Hopital Avicenne
  • Bordeaux, France
    • Recruiting
    • CHU de Bordeaux - Hôpital Haut-Lévêque
    • Contact: Maud Monsaingeon-Henry, MD; Email: maud.monsaingeon-henry@chu-bordeaux.fr
  • Boulogne-Billancourt, France
    • Recruiting
    • AP-HP - Hôpital Ambroise-Paré
    • Contact: Marion Bretault, MD; Email: marion.bretault@aphp.fr
  • Colombes, France
    • Recruiting
    • AP-HP - hôpital Louis-Mourier
    • Contact: Séverine LEDOUX, MD; Email: severine.ledoux@aphp.fr
  • Créteil, France
    • Recruiting
    • Centre Hospitalier Intercommunal de Créteil
    • Contact: Perle Sayedoff, MD; Email: perle.sayedoff@chicreteil.fr
  • Lille, France
    • Recruiting
    • CHU de LILLE - Hopital Claude Huriez
    • Contact: Hélène Verkindt, MD; Email: helene.verkindt@chu-lille.fr
  • Marseille, France
    • Recruiting
    • AP-HM - Hopital de La Conception
    • Contact: Bénédicte GABORIT, MD; Email: benedicte.gaborit@ap-hm.fr
  • Marseille, France
    • Withdrawn
    • AP-HM - Hôpital Nord
  • Paris, France
    • Recruiting
    • Institut Mutualiste Montsouris
    • Contact: Guillaume Pourcher, MD; Email: guillaume.pourcher@imm.fr
  • Paris, France, 75015
    • Recruiting
    • AP-HP - hôpital européen Georges-Pompidou
    • Contact: Claire Carette, MD; Email: claire.carette@aphp.fr
  • Paris, France
    • Recruiting
    • AP-HP - hôpital Bichat-Claude Bernard
    • Contact: Boris Hansel, MD; Email: boris.hansel@aphp.fr
  • Paris, France
    • Recruiting
    • AP-HP - hôpital de la Pitié-Salpêtrière
    • Contact: Judith Aron-Wisnewsky, MD; Email: judith.aron-wisnewsky@aphp.fr
  • Pierre-Bénite, France
    • Recruiting
    • HCL - Centre Hospitalier Lyon-Sud
    • Contact: Emmanuel Disse, MD; Email: emmanuel.disse@chu-lyon.fr
  • Saint-Denis, France
    • Not yet recruiting
    • CH de Saint-Denis - hôpital Delafontaire
    • Contact: Jean-Marc Catheline, MD; Email: jeanmarc.catheline@ch-stdenis.fr
  • Toulouse, France
    • Recruiting
    • CHU de Toulouse - Hopital Larrey
    • Contact: Patrick Ritz, MD; Email: ritz.p@chu-toulouse.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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.	Other: Standard Care; Standard Care; Drug: Metformin; Metformin will start at dose of 850 mg once daily and, at one month increased to 850 mg twice daily; 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)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Ministry of Health, France
• Investigators: Principal Investigator: Claire CARETTE, MD, claire.carette@aphp.fr

Study record dates

Study Major Dates

• Study Start (Actual): January 7, 2021
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): November 1, 2026

Study Registration Dates

• First Submitted: September 28, 2020
• First Submitted That Met QC Criteria: October 5, 2020
• First Posted (Actual): October 9, 2020

Study Record Updates

• Last Update Posted (Actual): June 8, 2023
• Last Update Submitted That Met QC Criteria: June 7, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Diabetes; Metformin; Bariatric Surgery; Sleeve gastrectomy; Gastric bypass
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: P170901J; 2019-000312-28 (EudraCT Number); PHRCN-17-0337 (Other Grant/Funding Number: French ministry of Health)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data (IPD) that underlie results in publication could be shared. IPD detailed in the protocol could be shared for the purpose of a metaanalysis.
• IPD Sharing Time Frame: Two years after the last publication

IPD Sharing Access Criteria

Data sharing must be accepted by the sponsor and the principal investigator (PI) based on a scientific project and scientific involvement of the PI team. Collaboration will be fostered.

Teams wishing obtain IPD must meet the sponsor and PI team to present scientifics (and commercial) purpose, IPD needed, format of data transmission, and timeframe. Technical feasibility and financial support will be discussed before mandatory contractualization. Processing of shared data must comply with European General Data Protection Regulation (GDPR).

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No