Menopausal Hormone Therapy, GLP-1 Agonists, and Glucose and Energy Homeostasis in Postmenopausal Women With Diabetes (DECLARED-CT)

Lia Bally

Status: Enrolling

Conditions: Menopause; Type 2 Diabetes

Treatments: Drug: Menopausal Hormone Therapy; Drug: GLP-1 Receptor Agonist

Study type: Interventional

Funder types: Other

Identifiers

NCT06715514

2024-01882 (Other Grant/Funding Number)

DECLARED-CT

10000574 (Other Grant/Funding Number)

Details and patient eligibility

About

The overall aim is to investigate the hypothesis that restoring E2 levels through MHT improves glucose and energy homeostasis and potentiates the beneficial effects of GLP-1RA in early postmenopausal women with pre- or existing type 2 diabetes.

The primary objective is to assess the efficacy of combined MHT and GLP-1RA in improving glucose control in early postmenopausal women with pre- or existing type 2 diabetes, compared to GLP-1RA alone. Secondary objectives include efficacy analyses on body weight, other measures of cardiometabolic health, lifestyle behaviour, menopausal symptoms, and the exploration of mechanisms underpinning potential glycaemic and weight control benefits, and biomarkers of haemostasis.

Full description

The menopausal-related decline in estradiol (E2) levels challenges glucose and energy homeostasis, exemplified by an increased risk of diabetes development or worsening of glucose in pre-existing diabetes. Conversely, restoration of E2 exposure using menopausal hormonal therapy (MHT) benefits body weight and glucose control. However, underlying mechanisms remain incompletely understood. In this context, we hypothesize an involvement of the GLP-1 gut-pancreas/brain axis, but supporting clinical evidence is currently lacking.

The overall aim is to investigate the hypothesis that restoring E2 levels through MHT improves glucose and energy homeostasis and potentiates the beneficial effects of GLP-1RA in early postmenopausal women with pre- or existing type 2 diabetes.

The primary objective is to assess the efficacy of combined MHT and GLP-1RA in improving glucose control in early postmenopausal women with pre- or existing type 2 diabetes, compared to GLP-1RA alone. Secondary objectives include efficacy analyses on body weight, other measures of cardiometabolic health, lifestyle behaviour, menopausal symptoms, and the exploration of mechanisms underpinning potential glycaemic and weight control benefits, and biomarkers of haemostasis.

Enrollment: 96 estimated patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Individuals fulfilling at enrolment all of the following inclusion criteria are eligible for the study:

• Early postmenopausal status (STRAW+10 stage +1b or +1c and FSH>25.0mU/L)
• Presence of menopausal symptoms (total MRS-II score ≥1)
• BMI ≥ 27.0kg/m2
• Pre- or existing type 2 diabetes (HbA1c 5.7%-8.5%)
• No prior or current use of MHT

The presence of any of the following exclusion criteria will lead to exclusion of the individuals:

• DPP4-inhibitor, SLGT2-inhibitor or sulfonylurea use within 8 weeks prior to study enrolment
• GLP-1RA use within 6 months prior to study enrolment
• Insulin therapy within 8 weeks prior to study enrolment
• History of bariatric surgery
• More than 2% change in body weight within three months prior to study enrolment (based on documented or reported weights)
• Contraindications for the use of the study medication as per prescription labelling: Personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2
• Known or suspected cancer of breast or other sexual organ, abnormal genital bleeding of unknown cause, hepatic neoplasia
• Arterial or venous thromboembolic events, porphyria
• Known allergy or hypersensitivity to Wegovy®, Estradot® or Utrogestan® (pharmaceutical agents or any of the excipients)
• Systemic hormone therapy or hormonal contraceptives (e.g. estrogens, progestogens, androgens) during the study and within 12 months prior to participation
• Herbal remedies and complimentary medicines for menopausal symptoms during the study
• Physical or psychological condition or any medical intervention (including medication not specified above) likely to interfere with the normal conduct of the study and interpretation of the study results as judged by the investigator
• Participation in another clinical trial that interferes with the interpretation of the study results
• Inability to read German
• Unwillingness to follow the study procedures

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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96 participants in 3 patient groups

Menopausal Hormone Therapy

Other group

Description:

Estradot®: 50 micrograms/24h, transdermal patch E2; Utrogestan®\*: once daily 200mg of micronized progesterone (in women with intact uterus\*)

Treatment:

Drug: Menopausal Hormone Therapy

GLP-1 Receptor Agonist

Active Comparator group

Description:

Wegovy®: Semaglutide injected once weekly, starting dose 0.25mg, with dose increments every four weeks reaching the maintenance dose of 1mg after eight weeks

Treatment:

Drug: GLP-1 Receptor Agonist

Combined Menopausal Hornome Therapy and GLP-1 Receptor Agonist

Experimental group

Description:

Wegovy®: Semaglutide injected once weekly, starting dose 0.25mg, with dose increments every four weeks reaching the maintenance dose of 1mg after eight weeks; Estradot®: 50 micrograms/24h, transdermal patch E2; Utrogestan®\*: once daily 200mg of micronized progesterone (in women with intact uterus)

Treatment:

Drug: Menopausal Hormone Therapy

Drug: GLP-1 Receptor Agonist