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

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.

• Need for glucose-lowering (rescue) therapy [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 [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 [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 [Time frame: Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)]
• BMI [Time frame: Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)]
• Waist circumference [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 [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 [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 [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 [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®) [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 [Time frame: Assessed at 160 weeks (end of treatment) and at 172-184 weeks (3-6 months after discontinuation of study medication)]