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.
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
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
TRIPLE
Enrollment
252
maintenance dose of 1mg SC once weekly
maintenance dose of 1mg SC once weekly
AZORG
Aalst, Belgium
RECRUITINGUZA
Antwerp, Belgium
RECRUITINGZAS
Antwerp, Belgium
RECRUITINGAZ St Jan Brugge
Bruges, Belgium
RECRUITINGErasme
Brussels, Belgium
RECRUITINGUZ Brussel
Brussels, Belgium
RECRUITINGJan Yperman
Ieper, Belgium
RECRUITINGAZ Groeninge Kortrijk
Kortrijk, Belgium
RECRUITINGUZ Leuven
Leuven, Belgium
RECRUITINGCHU de Liège
Liège, Belgium
RECRUITING...and 3 more locations
Development of T2DM
Defined by FPG, OGTT, and/or HbA1c according to the ADA criteria
Time frame: by 160 weeks
Need for glucose-lowering (rescue) therapy
Percentage need for rescue therapy for diabetes
Time frame: 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
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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
Time frame: 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%
Time frame: 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%
Time frame: 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%
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: 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
Time frame: 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).
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)
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