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 13 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)] 6weeks - 12 months 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 plasma glucose, OGTT and/or HbA1c according to the ADA criteria. Important secondary endpoints are assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication) and include:

Glycaemic outcomes

• Need for glucose-lowering (rescue) therapy;
• Frequency of prediabetes based on FPG, OGTT, and/or HbA1c;
• Regression to normoglycaemia. Anthropometric and body composition outcomes
• Change in body weight, BMI, waist circumference, waist-to-hip ratio;
• Proportion of participants achieving ≥5%, ≥10%, and ≥15% weight loss;
• Body fat percentage assessed by bioelectrical impedance analysis (Bodystat 1500®).

Insulin sensitivity and β-cell function

• β-cell function, assessed by HOMA-B, insulinogenic index divided by HOMA-IR, insulin secretion-sensitivity index-2, and the Stumvoll index;
• Insulin sensitivity, assessed by the Matsuda index (reflecting whole body insulin sensitivity) and 1/HOMA-IR, reflecting primarily hepatic insulin sensitivity.

Cardiometabolic risk factors

• Prevalence of the metabolic syndrome;
• Blood pressure (blood pressure ≥140/90 mmHg) and heart rate;
• Lipid profile, including low density lipoprotein-cholesterol (LDL-cholesterol, ≥100 mg/dL or ≥2,6 mmol/L) and triglycerides (≥150 mg/dL or ≥1,7 mmol/L).

Patient-reported outcomes

• Health-related quality of life assessed by SF-36 and EQ-5D-5L;
• Symptoms of depression (CES-D) and anxiety (short-form STAI);
• Treatment satisfaction assessed using a study-specific questionnaire based on the Diabetes Treatment Satisfaction Questionnaire;
• Sleep quality (Pittsburgh Sleep Quality Index) and food security (short-form HFSSM).

Biomarker outcomes

• Changes in and associations of metabolomic profiles, with cardiometabolic risk and treatment response.

Health economic outcomes

• Quality-adjusted life years (QALYs);
• Incremental costs and incremental cost-effectiveness ratio (ICER) of semaglutide compared with placebo.
• Health economic analyses are considered exploratory and hypothesis-generating, as the study was primarily powered for the clinical endpoint of incident T2DM rather than economic outcomes.

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
    • AZORG
    • Contact: Katrien Wierckx
  • Antwerp, Belgium
    • Recruiting
    • UZA
    • Contact: Niels Bochanen
  • Antwerp, Belgium
    • Recruiting
    • ZAS
    • Contact: Ann Verhaegen
  • Bruges, Belgium
    • Recruiting
    • AZ St Jan Brugge
    • Contact: Sara Vandewalle, MD; Phone Number: 003250 45 23 3; Email: SARA.VANDEWALLE@azsintjan.be
  • Brussels, Belgium
    • Recruiting
    • UZ Brussel
    • Contact: Nancy Van Wilder
  • Brussels, Belgium
    • Recruiting
    • Erasme
    • Contact: Maria Lytrivi
  • Ieper, Belgium
    • Recruiting
    • Jan Yperman
    • Contact: An Nollet, MD; Phone Number: 003257 35 72 70; Email: an.nollet@yperman.net
  • 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
  • Sint-Niklaas, Belgium
    • Recruiting
    • Vitaz
    • Contact: Peter Coremans
  • Turnhout, Belgium
    • Recruiting
    • AZ Turnhout
    • Contact: Joke Cuypers, MD; Phone Number: 003214 44 44 32; Email: joke.cuypers@azturnhout.be

Participation Criteria

Eligibility Criteria

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

Description

Eligible participants are women aged ≥18 years, with a history of GDM diagnosed according to the 2013 WHO criteria (at 24-32 weeks gestation or <24 weeks for early GDM). Participants must have prediabetes diagnosed between 6 weeks and 12 months postpartum according to ADA criteria (FPG 5.6-6.9 mmol/L, 2-hour OGTT glucose 7.8-11.0 mmol/L and/or HbA1c 39-46 mmol/mol [5.7-6.4%]).

Additional inclusion criteria include cessation of breastfeeding, no intention to become pregnant within the next year, use of effective contraception and no use of medication affecting glucose metabolism. Written ICF is obtained prior to any study-related procedures.

Exclusion criteria include established diabetes, presence of autoantibodies suggestive of type 1 diabetes, normal glucose tolerance, history of pancreatitis, previous bariatric surgery or planned surgery within two years, unable to understand and speak Dutch, French or English and current pregnant or planning to become pregnant within one year after participating in the study.

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
Development of T2DM	Defined by FPG, OGTT, and/or HbA1c according to the ADA criteria	by 160 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Need for glucose-lowering (rescue) therapy	Percentage need for rescue therapy for diabetes	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Frequency of prediabetes based on FPG, OGTT, and/or HbA1c	Percentage of prediabetes based on FPG, OGTT, and/or HbA1c	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Regression to normoglycaemia	Percentage regression to normoglycaemia, based on fasting glycaemia, oral glucose tolerance test and/or HbA1c (ADA criteria)	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Change in body weight	Change in body weight (kg)	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
BMI	Mean BMI (Kg/m2)	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Waist circumference	Mean waist circumference (cm)	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Waist-to-hip ratio	Waist/hip circumference ratio	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Proportion of participants achieving ≥5% weight loss	Percentage weight loss ≥5%	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Proportion of participants achieving ≥10% weight loss	Percentage weight loss ≥10%	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Proportion of participants achieving ≥15% weight loss	Percentage weight loss ≥15%	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Body fat percentage assessed by bioelectrical impedance analysis (Bodystat 1500®)	Percentage body fat measured by bioelectrical impedance analysis	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
β-cell function, assessed by HOMA-B	Beta-cell function measured by the HOMA-B index	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Insulinogenic index divided by HOMA-IR	Beta-cell function measured by the by the insulinogenic index divided by HOMA-insulin resistance index	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Insulin secretion-sensitivity index-2	Beta-cell function measured by theby the insulin-secretion sensitivity-2 index	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Stumvoll index	Beta-cell function measured by the Stumvoll index	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Insulin sensitivity, assessed by the Matsuda index (reflecting whole body insulin sensitivity)	Whole body Insulin sensitivity measured by the insulin sensitivity index of Matsuda	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
1/HOMA-IR, reflecting primarily hepatic insulin sensitivity	The reciprocal of the homeostasis model assessment of insulin resistance (1/HOMA-IR)	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Prevalence of the metabolic syndrome	Percentage of the metabolic syndrome based on the WHO criteria	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Blood pressure (blood pressure ≥140/90 mmHg)	Percentage blood pressure ≥140/90mmHg	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Heart rate	Mean heart rate	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Lipid profile, including low density lipoprotein-cholesterol (LDL-cholesterol, ≥100 mg/dL or ≥2,6 mmol/L)	Percentage LDL cholesterol ≥100mg/dl or ≥2,6 mmol/L	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Lipid profile, including triglycerides (≥150 mg/dL or ≥1,7 mmol/L)	Percentage triglycerides ≥150mg/dl or ≥1,7 mmol/L	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Health-related quality of life assessed by SF-36	Health-related quality of life assessed using the 36-Item Short Form Health Survey (SF-36). Scores range from 0 to 100, with higher scores indicating better health-related quality of life	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Health-related quality of life assessed by EQ-5D-5L	Health-related quality of life assessed using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale (EQ VAS). Scores range from 0 to 100, with higher scores indicating better perceived health status	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Symptoms of depression (CES-D)	Depressive symptoms assessed using the 20-item Center for Epidemiologic Studies Depression Scale (CES-D). Total scores range from 0 to 60, with higher scores indicating more depressive symptoms	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Symptoms of anxiety (short-form STAI)	Symptoms of anxiety assessed using the 6-item short-form State-Trait Anxiety Inventory (STAI). Total scores range from 20 to 80 after score transformation, with higher scores indicating greater anxiety symptoms	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Treatment satisfaction assessed using a study-specific questionnaire based on the Diabetes Treatment Satisfaction Questionnaire	Diabetes risk perception assessed using the Diabetes Risk Perception Questionnaire, a validated questionnaire that evaluates perceived risk of developing diabetes	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Sleep quality (Pittsburgh Sleep Quality Index)	Sleep quality assessed using the validated Pittsburgh Sleep Quality Index (PSQI)	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Food security (short-form HFSSM)	Food security assessed using the short-form Household Food Security Survey Module (HFSSM). Scores indicate the level of food security, with higher scores reflecting greater food insecurity	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Plasma metabolite concentrations	Changes in and associations of metabolomic profiles, with cardiometabolic risk and treatment response. Assessed using metabolomic profiling. Blood samples will be collected at baseline and every 6 months during a 3.5-year follow-up period (study visits).	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Quality-adjusted life years (QALYs)	Quality-adjusted life years (QALYs), calculated as the area under the curve of health-related quality of life utility values over time, where higher values indicate better health outcomes	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Incremental costs and incremental cost-effectiveness ratio (ICER) of semaglutide compared with placebo	Incremental costs and incremental cost-effectiveness ratio (ICER) of semaglutide versus placebo	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
Incremental healthcare costs	Incremental healthcare costs associated with the intervention compared with control, calculated from collected healthcare resource utilization and unit cost data. Currency (e.g., EUR per participant)	Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Collaborators: Universitair Ziekenhuis Brussel; University Hospital, Antwerp; Onze Lieve Vrouw Hospital; General Hospital Groeninge; AZ Turnhout; Erasme University Hospital; AZ Sint-Lucas Brugge; Centre Hospitalier Universitaire de Liege; Vitaz; Centre Hospitalier Mouscron; Jan Yperman Ziekenhuis; Ziekenhuis aan de Stroom

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2023
• Primary Completion (Estimated): June 1, 2029
• Study Completion (Estimated): December 1, 2029

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): July 7, 2026
• Last Update Submitted That Met QC Criteria: July 2, 2026
• Last Verified: April 1, 2026

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: Urogenital Diseases; Endocrine System Diseases; Female Urogenital Diseases and Pregnancy Complications; Metabolic Diseases; Pregnancy Complications; Glucose Metabolism Disorders; Diabetes Mellitus; Nutritional and Metabolic Diseases; Diabetes, Gestational; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor Agonists; Physiological Effects of Drugs; Hypoglycemic Agents; semaglutide
• 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)?: YES
• IPD Plan Description: Individual participant data will be made available upon reasonable request after study completion, database lock, unblinding, and publication of the primary results, subject to applicable ethical, legal, and data protection requirements.

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