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

Not Applicable

Recruiting

• Conditions: Menopause; Type 2 Diabetes
• Interventions: Drug: Menopausal Hormone Therapy; Drug: GLP-1 Receptor Agonist

• Registration Number: NCT06715514
• Lead Sponsor: Lia Bally

Brief Summary

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.

Detailed 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.

Study Timeline

• Study First Submitted: 2024-11-28
• Study First Submitted QC: 2024-11-28
• Study First Posted: 2024-12-04
• Study Start: 2025-02-18
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-03
• Last Update Posted: 2025-03-06
• Primary Completion: 2026-08-31
• Study Completion: 2026-08-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Female
• Target Recruitment: 96

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Menopausal Hormone Therapy	Menopausal Hormone Therapy	Estradot®: 50 micrograms/24h, transdermal patch E2; Utrogestan®\*: once daily 200mg of micronized progesterone (in women with intact uterus\*)
GLP-1 Receptor Agonist	GLP-1 Receptor Agonist	Wegovy®: Semaglutide injected once weekly, starting dose 0.25mg, with dose increments every four weeks reaching the maintenance dose of 1mg after eight weeks
Combined Menopausal Hornome Therapy and GLP-1 Receptor Agonist	GLP-1 Receptor Agonist	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)
Combined Menopausal Hornome Therapy and GLP-1 Receptor Agonist	Menopausal Hormone Therapy	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)

Primary Outcome Measures

Name	Time	Method
Change in HbA1C	12 Weeks	Change in HbA1C from Baseline (Visit 1a) to Visit 2a (units: percentage points). The primary outcome will be compared between the combined MHT+GLP-1RA arm and the GLP-1RA only arm.

Secondary Outcome Measures

Name	Time	Method
Change in average sensor glucose levels	12 Weeks	The change will be quantified as the difference in average sensor glucose levels from the Baseline assessment period (14 days prior to end of Visit 1a) to the last 14 days of the intervention period (i.e., the 14 days before Visit 2a) (units: mmol/L).
Change in time with sensor glucose in tight target range [3.9-7.8 mmol/L]	12 Weeks	The change, measured in percentage points, will be quantified as the difference in the percentage of time with sensor glucose in the tight target range \[3.9-7.8 mmol/L\] from the Baseline assessment period (14 days prior to end of Visit 1a) to the last 14 days of the intervention period (i.e., the 14 days before Visit 2a).
Change in fasting plasma glucose levels	12 Weeks	The change will be quantified as the difference in fasting plasma glucose levels from Baseline (Visit 1a) to Visit 2a (units: mmol/L).
Change in body weight	12 Weeks	The change from Baseline (Visit 1a) to Visit 2a will be evaluated (units: kg).
Change in body fat percentage	12 Weeks	The change in percentage of body fat from Baseline (Visit 1a) to Visit 2a will be evaluated (units: percentage points). The percentage of body fat will be obtained from BIA measurements.
Change in non-HDL cholesterol	12 Weeks	The change in non-HDL cholesterol from Baseline (Visit 1a) to Visit 2a will be evaluated (units mmol/L). Non-HDL cholesterol will be quantified as the difference between total cholesterol and HDL cholesterol.
Change in systolic blood pressure	12 Weeks	The change in systolic blood pressure from Baseline (Visit 1a) to Visit 2a will be evaluated (units: mmHg).
Change in liver fat (controlled attenuation parameter)	12 Weeks	The change in the controlled attenuation parameter from Baseline (Visit 1a) to Visit 2a will be evaluated (units: dB/m). Liver fat will be quantified using transient elastography.
Change in whole-body insulin sensitivity	12 Weeks	The change in whole-body insulin sensitivity from Baseline (Visit 1a) to Visit 2a will be evaluated (units: 10e-5 dL/(kg\*min) per pmol/L). Whole-body insulin sensitivity will be quantified using the Oral Glucose Minimal Model method on the OGTT data.
Change in quality of life	12 Weeks	The change in the quality of life from Baseline (Visit 1a) to Visit 2a will be evaluated (units: arbitrary units). Quality of life will be assessed using the total score of the EQ-5D-5L questionnaire.
Change in postmenopausal symptoms burden	12 Weeks	The change in the postmenopausal symptoms burden from Baseline (Visit 1a) to Visit 2a will be evaluated (units: arbitrary units). Postmenopausal symptom burden will be assessed using the total score of the Menopausal Rating Scale (MRS-II).
Change in frequency of vasomotor symptoms	12 Weeks	The change in the frequency of vasomotor symptoms from Baseline (Visit 1a) to Visit 2a will be evaluated (units: number per day). The frequency of vasomotor symptoms will be assessed using an electronic diary during 24 hours prior to Visit 1a and Visit 2a.
Change in intensity of vasomotor symptoms	12 Weeks	The change in the intensity of vasomotor symptoms from Baseline (Visit 1a) to Visit 2a will be evaluated (units: intensity per episode).The intensity of vasomotor symptoms will be assessed using the intensity scale for hot flashes in the Menopausal Rating Scale (MRS-II). It will be recorded in an electronic diary during 24 hours prior to Visit 1a and Visit 2a.
Change in postprandial plasma glucose exposure during the OGTT (AUC plasma glucose concentration)	12 Weeks	Change in postprandial plasma glucose exposure from Baseline (Visit 1a) to Visit 2a. Postprandial glucose exposure will be quantified by the area under the plasma glucose concentration curve from glucose intake (T0) until 240 minutes following glucose intake. The resulting values will be normalized to the duration of the experiment and reported in mmol/L.

Trial Locations

Locations (1)

University Hospital Bern; 🇨🇭 Bern, Switzerland