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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Glucose Intolerance After a Recent History of Gestational Diabetes
• Intervention / Treatment: Drug: Semaglutide Pen Injector; Drug: Semaglutide placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 252
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Katrien Benhalima, MD PhD; Phone Number: 32 16340614; Email: katrien.benhalima@uzleuven.be

Study Locations

• Belgium
  • Aalst, Belgium
    • Recruiting
    • OLV-Aalst-Asse
    • Contact: Katrien Wierckx
  • Antwerp, Belgium
    • Not yet recruiting
    • UZA
    • Contact: Niels Bochanen
  • Antwerp, Belgium
    • Not yet recruiting
    • ZNA,
    • Contact: Ann Verhaegen
  • Brussel, Belgium
    • Not yet recruiting
    • UZ Brussel
    • Contact: Nancy Van Wilder
  • Brussel, Belgium
    • Not yet recruiting
    • Erasme
    • Contact: Maria Lytrivi
  • Kortrijk, Belgium
    • Recruiting
    • AZ Groeninge Kortrijk
    • Contact: Gertjan Vereecke
  • Leuven, Belgium
    • Recruiting
    • UZ Leuven
    • Contact: Katrien Benhalima
  • Liège, Belgium
    • Recruiting
    • CHU de Liège
    • Contact: JC Philips
  • Mouscron, Belgium
    • Recruiting
    • Centre Hospitalier Mouscron
    • Contact: Philippe Oriot
  • Roeselare, Belgium
    • Recruiting
    • AZ Delta Roeselare
    • Contact: Xavier-Philippe Aers
  • Sint-Niklaas, Belgium
    • Recruiting
    • VITAZ
    • Contact: Peter Coremans

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Voluntary written informed consent of the participant has been obtained prior to any screening procedures
2. Use of highly effective methods of birth control
3. 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)
4. 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: semaglutide; 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; maintenance dose of 1mg SC once weekly; Other Names: Ozempic
Placebo Comparator: placebo; placebo SC once weekly, the same dose-escalation regimen, using matching injections, treatment duration of max. 3 years	Drug: Semaglutide placebo; maintenance dose of 1mg SC once weekly

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Collaborators: Jessa Hospital; Universitair Ziekenhuis Brussel; University Hospital, Antwerp; AZ Delta; Onze Lieve Vrouw Hospital; General Hospital Groeninge; Ziekenhuis Netwerk Antwerpen (ZNA); Erasme University Hospital; Centre Hospitalier Universitaire de Liege; Vitaz; Centre Hospitalier Mouscron

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2023
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: September 28, 2022
• First Submitted That Met QC Criteria: October 3, 2022
• First Posted (Actual): October 6, 2022

Study Record Updates

• Last Update Posted (Actual): September 18, 2023
• Last Update Submitted That Met QC Criteria: September 14, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: GLP-1 agonist; semaglutide; prevention; type 2 diabetes; gestational diabetes; glucose intolerance postpartum
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Pregnancy Complications; Hyperglycemia; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Diabetes Mellitus; Glucose Intolerance; Diabetes, Gestational
• Other Study ID Numbers: S66967; 2022-502082-22-00 (Other Identifier: EU CT number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No