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NCT Number: NCT06715514

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

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.

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Key information

Conditions

Menopause Diabetes Mellitus Diabetes Mellitus, Type 2 Endocrine System Diseases Glucose Metabolism Disorders Metabolic Diseases Nutritional and Metabolic Diseases Type 2 Diabetes

Age range

18 year and older

Sex eligibility

Female

Study type

Interventional

Phase

Not applicable

Primary location

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

GLP-1 receptor agonist

Drug

Wegovy®

Other names: Semaglutide

Menopausal hormone therapy

Drug

Estradot® and Utrogestan®* (in women with intact uterus*)

Other names: Estradiol, Micronized Progesterone

Primary outcomes

  1. Change in HbA1C

    Time frame: 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 outcomes

  1. Change in postprandial plasma glucose exposure during the OGTT (AUC plasma glucose concentration)

    Time frame: 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.

  2. Change in average sensor glucose levels

    Time frame: 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).

  3. Change in time with sensor glucose in tight target range [3.9-7.8 mmol/L]

    Time frame: 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).

  4. Change in fasting plasma glucose levels

    Time frame: 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).

  5. Change in body weight

    Time frame: 12 Weeks

    The change from Baseline (Visit 1a) to Visit 2a will be evaluated (units: kg).

  6. Change in body fat percentage

    Time frame: 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.

  7. Change in non-HDL cholesterol

    Time frame: 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.

  8. Change in systolic blood pressure

    Time frame: 12 Weeks

    The change in systolic blood pressure from Baseline (Visit 1a) to Visit 2a will be evaluated (units: mmHg).

  9. Change in liver fat (controlled attenuation parameter)

    Time frame: 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.

  10. Change in whole-body insulin sensitivity

    Time frame: 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.

  11. Change in quality of life

    Time frame: 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.

  12. Change in postmenopausal symptoms burden

    Time frame: 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).

  13. Change in frequency of vasomotor symptoms

    Time frame: 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.

  14. Change in intensity of vasomotor symptoms

    Time frame: 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.

Other outcomes

  1. Change in incretin effect

    Time frame: 12 Weeks

    Incretin effect (OGTT-IIGI difference in the insulin secretion AUC). The change in OGTT-IIGI insulin secretion AUC from Visit 1 (Visit 1a and Visit 1b) to Visit 2 (Visit 2a and Visit 2b) will be evaluated (units: percentage points). The direct incretin effect will only be assessed in the MHT only arm.

  2. Change in gastric emptying

    Time frame: 12 Weeks

    The change in gastric emptying from Baseline (Visit 1a) to Visit 2a will be quantified by the half-emptying time (units: min). Gastric emptying will be calculated from the 13CO2 enrichment in breath samples collected during the OGTT.

  3. Change in glucose rate of appearance

    Time frame: 12 Weeks

    The change in glucose rate of appearance from Baseline (Visit 1a) to Visit 2a will be evaluated (units: percentage points). Glucose rate of appearance will be quantified using the Oral Minimal Model Method on the OGTT data.

  4. Change in beta-cell function

    Time frame: 12 Weeks

    The change in beta-cell function from Baseline (Visit 1a) to Visit 2a will be evaluated (units: 10e-9/min). Beta-cell function will be quantified using the Oral Minimal Model Method on the OGTT data.

  5. Change in beta-cell glucose responsivity

    Time frame: 12 Weeks

    The change in beta-cell glucose responsivity from Baseline (Visit 1a) to Visit 2a will be evaluated (units: 10e-9/min). Beta-cell glucose responsivity will be quantified using the Oral Minimal Model Method on the OGTT data.

  6. Change in GLP-1 secretion

    Time frame: 12 Weeks

    The change in GLP-1 secretion from Baseline (Visit 1a) to Visit 2a will be evaluated (units: pmol/L*min*10e2). GLP-1 secretion will be quantified using the Oral Minimal Model coupled to an oral model of GLP-1 action on the OGTT data.

  7. Change in beta-cell GLP-1 sensitivity

    Time frame: 12 Weeks

    The change in beta-cell GLP-1 sensitivity from Baseline (Visit 1a) to Visit 2a will be evaluated (units: %/[pmol/L]). Beta-cell GLP-1 sensitivity will be quantified using the Oral Minimal Model coupled to an oral model of GLP-1 action on the OGTT data.

  8. Change in GLP-1 potentiation of insulin secretion

    Time frame: 12 Weeks

    The change in GLP-1 potentiation of insulin secretion from Baseline (Visit 1a) to Visit 2a will be evaluated (units: (%*min*10e2). GLP-1 potentiation of insulin secretion will be quantified using the Oral Minimal Model coupled to an oral model of GLP-1 action on the OGTT data.

  9. Change in production ("hepatic") insulin sensitivity

    Time frame: 12 Weeks

    The change in production insulin sensitivity from Baseline (Visit 1a) to Visit 2a will be evaluated (units: 10e-5 dL/(kg*min) per pmol/L). Production insulin sensitivity will be quantified using the single-tracer Oral Minimal Model method on the OGTT data.

  10. Change in disposal ("peripheral") insulin sensitivity

    Time frame: 12 Weeks

    The change in disposal insulin sensitivity from Baseline (Visit 1a) to Visit 2a will be evaluated (units: 10e-5 dL/(kg*min) per pmol/L). Disposal insulin sensitivity will be quantified using the single-tracer Oral Minimal Model method on the OGTT data.

  11. Change in energy intake

    Time frame: 12 Weeks

    The change in energy intake from Baseline (Baseline assessment period) to the Intervention period will be evaluated (units: kJ/day). Energy intake will be derived from an energy balance model based on body weight data collected using the smart scale during the baseline and the intervention periods.

  12. Change in resting energy expenditure

    Time frame: 12 Weeks

    The change in resting energy expenditure from Baseline (Visit 1a) to Visit 2a will be evaluated (units: kJ/day). Resting energy expenditure will be measured by indirect calorimetry.

  13. Change in total energy expenditure

    Time frame: 12 Weeks

    The change in total energy expenditure from Baseline (Baseline assessment period) to the Intervention period will be evaluated (units: kJ/day). Total energy expenditure will be obtained from the smartwatch data (using Garmin's proprietary algorithm) during the baseline and the intervention periods.

  14. Change in meal frequency

    Time frame: 12 Weeks

    The change in meal frequency from Baseline (Baseline assessment period) to the Intervention Period will be evaluated (units: meals/day). Meal frequency will be assessed using the automated food analysis app SNAQ.

  15. Change in diet composition

    Time frame: 12 Weeks

    The change in diet composition from Baseline (Visit 1a) to Visit 2a will be evaluated (units: Percentage points). Diet composition will be assessed using the Swiss Food Frequency Questionnaire.

Study contacts

Contact information is provided by the study sponsor or research team.

Prof. Dr. med. et Dr. phil.Lia Bally

CONTACT

[email protected]

+41 31 632 36 77

Sponsors and collaborators

Lead sponsor

Lia Bally

Other

Registry information

Official study title

Effects of Combined Menopausal Hormone Therapy and GLP-1 Receptor Agonist Therapy on Glucose and Energy Homeostasis in Early Postmenopausal Women With or at Risk of Diabetes

Acronym: DECLARED-CT

Important dates

Study start
2025
Primary completion
2026
Study completion
2026
First posted
Dec 4, 2024
Registry last updated
Jun 5, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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