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

Universitaire Ziekenhuizen KU Leuven

Status and phase: Enrolling; Phase 3

Conditions: Glucose Intolerance After a Recent History of Gestational Diabetes

Treatments: Drug: Semaglutide placebo; Drug: Semaglutide Pen Injector

Study type: Interventional

Funder types: Other

Identifiers

NCT05569772

2022-502082-22-00 (Other Identifier)

S66967

Details and patient eligibility

About

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.

Full 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.

Enrollment: 252 estimated patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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252 participants in 2 patient groups, including a placebo group

semaglutide

Active Comparator group

Description:

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

Treatment:

Drug: Semaglutide Pen Injector

placebo

Placebo Comparator group

Description:

placebo SC once weekly, the same dose-escalation regimen, using matching injections, treatment duration of max. 3 years

Treatment:

Drug: Semaglutide placebo