Semaglutide for the Treatment of Glucose Intolerance in Women With Prior Gestational Diabetes

Study Overview
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Brief Summary
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Gestational diabetes (GDM) is an important contributor to the increasing prevalence of type 2 diabetes (T2DM). Women with glucose intolerance in early postpartum are a particularly high-risk group with about 50% who will develop T2DM within 5 years after the delivery. Moreover, women with a history of GDM progress more rapidly to T2DM compared to women with similarly elevated glucose levels. Early intervention after the index pregnancy is therefore crucial to prevent T2DM. With the SERENA project, the investigators aim to reduce the risk to develop T2DM with the long-acting GLP-1 agonist semaglutide in women with a recent history of GDM and glucose intolerance in early postpartum.

Detailed Description
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Patient population: Women with a recent history of gestational diabetes (GDM) and persistent glucose intolerance in early postpartum are a particularly high risk group, with about 50% developing type 2 diabetes (T2DM) within 5 years after the delivery. Semaglutide is a long-acting glucagon-like peptide-1 (GLP-1) agonist with multiple beneficial metabolic effects, including glucose lowering effect, weight loss and cardiovascular protective effects. The investigators hypothesize that in women with prior GDM and glucose intolerance in early postpartum, treatment with semaglutide will reduce the risk to develop T2DM on the long-term compared to placebo. Intervention and comparison: Belgian multi-centric double blind RCT with 11 centers to compare semaglutide (once weekly) with placebo in women with a recent history of GDM and glucose intolerance [impaired fasting glycaemia (IFG) and/or impaired glucose tolerance (IGT)] 6-24 weeks postpartum. Participants will be 1/1 randomized to semaglutide or placebo on a background of lifestyle measures. Semaglutide will be uptitrated to 1mg/week over a 8-week period. Participants will be followed-up for 3 years. Participants will receive a 75g oral glucose tolerance test (OGTT) 3-6 months after the stop of the intervention. Randomization will be stratified according to BMI at the early postpartum visit (<25; 25-29.9 and ≥30Kg/m²). Outcomes: The primary endpoint is the development of T2DM by 160 weeks defined by fasting glycaemia, OGTT and/or HbA1c according to the ADA criteria. Important secondary endpoints include the need for rescue therapy for diabetes, regression to normoglycaemia, weight loss, beta-cell function, insulin resistance and the metabolic syndrome. To achieve 80% power, we plan a sample size of 252 to detect an estimated 50% reduction in the risk to develop T2DM between both groups, assuming a 30% loss to follow-up during the study.

Official Title
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Semaglutide for the Treatment of Glucose Intolerance in Women With Prior Gestational Diabetes: a Double Blind RCT

Conditions
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Glucose Intolerance After a Recent History of Gestational Diabetes

Intervention / Treatment
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* Drug: Semaglutide Pen Injector
* Drug: Semaglutide placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary written informed consent of the participant has been obtained prior to any screening procedures Use of highly effective methods of birth control History of GDM (diagnosed with 2013 WHO criteria 24-32 weeks of pregnancy) and glucose intolerance 6-24 weeks postpartum (based on the ADA criteria) Needs to be able to understand and speak Dutch, French or English Exclusion Criteria: 1. Participant has a history of any type of diabetes or auto-antibodies for type 1 diabetes, history of pancreatitis, family or personal history of medullary thyroid carcinoma or personal history of thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, severe psychiatric disorder in the past year, heart failure NYHA class 4, end-stage renal disease (eGFR <15) or dialysis, or history of bariatric surgery 2. Any disorder, which in the Investigator's opinion might jeopardise the participant's safety or compliance with the protocol 3. Any prior or concomitant treatment(s) that might jeopardise the participant's safety or that would compromise the integrity of the Trial 4. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate, highly effective contraceptive 5. Participation in an interventional Trial with an investigational medicinal product or device 6. Age <18 years, breastfeeding >24 weeks postpartum or HbA1c≥6.5% at the time of the OGTT in pregnancy 7. Use of medication with significant impact on glycaemia (such as high dose glucocorticoids or metformin)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: multi-centric double blind RCT
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: semaglutide<br>semaglutide SC once weekly, up titration over 2 month period to 1mg/week (0.25mg once weekly, after 4 weeks 0.5mg once weekly and after 8 weeks the maintenance dose of 1mg once weekly), treatment duration of max. 3 years | Drug: Semaglutide Pen Injector<br>* maintenance dose of 1mg SC once weekly<br>* Other names: Ozempic;|
| Placebo Comparator: placebo<br>placebo SC once weekly, the same dose-escalation regimen, using matching injections, treatment duration of max. 3 years | Drug: Semaglutide placebo<br>* maintenance dose of 1mg SC once weekly<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| type 2 diabetes | development of type 2 diabetes defined by fasting glycaemia, oral glucose tolerance test and/or HbA1c according to the ADA criteria | by 160 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| medication for diabetes | percentage need for rescue therapy for diabetes | by 160 weeks | 
| prediabetes | percentage prediabetes based on fasting glycaemia, oral glucose tolerance test and/or HbA1c (ADA criteria) | by 160 weeks | 
| normoglycaemia | percentage regression to normoglycaemia, based on fasting glycaemia, oral glucose tolerance test and/or HbA1c (ADA criteria) | by 160 weeks | 
| BMI | mean BMI (Kg/m2) | by 160 weeks | 
| waist circumference | mean waist circumference (cm) | by 160 weeks | 
| waist/hip ratio | waist/hip circumference ratio | by 160 weeks | 
| 5% weight loss | percentage weight loss ≥5% | by 160 weeks | 
| 10% weight loss | percentage weight loss ≥10% | by 160 weeks | 
| 15% weight loss | percentage weight loss ≥15% | by 160 weeks | 
| body fat percentage | percentage body fat measured by bioelectrical impedance analysis | by 160 weeks | 
| HOMA-B index | Beta-cell function measured by the HOMA-B index | by 160 weeks | 
| insulinogenic index | Beta-cell function measured by the by the insulinogenic index divided by HOMA-insulin resistance index | by 160 weeks | 
| ISSI-2 index | Beta-cell function measured by theby the insulin-secretion sensitivity-2 index | by 160 weeks | 
| the Stumvoll index. | Beta-cell function measured by the Stumvoll index. | by 160 weeks | 
| Matsuda index | whole body Insulin sensitivity measured by the insulin sensitivity index of Matsuda | by 160 weeks | 
| HOMA-IR | the reciprocal of the homeostasis model assessment of insulin resistance (1/HOMA-IR) | by 160 weeks | 
| metabolic syndrome | percentage of the metabolic syndrome based on the WHO criteria | by 160 weeks | 
| Hypertension | percentage blood pressure ≥140/90mmHg | by 160 weeks | 
| heart rate | mean heart rate | by 160 weeks | 
| LDL cholesterol | percentage LDL cholesterol ≥100mg/dl | by 160 weeks | 
| Triglycerides | percentage triglycerides ≥150mg/dl | by 160 weeks | 
| hypoglycaemia | percentage with hypoglycaemia (<54mg/dl) | by 160 weeks | 
| gastro-intestinal side effects | percentage nausea, vomiting or diarrhea | by 160 weeks | 
| self-reported quality of life | health-related quality of life by SF-36 questionnaire | by 160 weeks | 
| symptoms of depression | the 20-item Center for Epidemiologic Studies-Depression (CES-D) questionnaire | by 160 weeks | 
| anxiety | six-item short-form of the State-Trait Anxiety Inventory questionnaire on anxiety (STAI) | by 160 weeks | 
| Diabetes risk perception | Diabetes Risk perception questionnaire, a validated questionnaire to evaluate the perception to develop diabetes | by 160 weeks | 
| sleep quality | The validated Pittsburg sleep quality index to evaluate sleep quality | by 160 weeks | 
| diabetes remission | diabetes remission rate after treatment stop, defined by fasting, OGTT and/or HbA1c | by 172-184 weeks (3-6 months after end of therapy) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gestational diabetes, glucose intolerance postpartum, prevention, type 2 diabetes, GLP-1 agonist, semaglutide