Clinical trial NCT06715514: Menopausal Hormone Therapy, GLP-1 Agonists, and Glucose and Energy Homeostasis in Postmenopausal Women With Diabetes
Official 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Menopause
Type 2 Diabetes
Keywords: Diabetes
Menopause
Menopausal Hormone Therapy
Womens Health
Randomized Controlled Trial
GLP-1 receptor agonist
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
First posted: 2024-12-04
Enrollment: 96
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: All efficacy outcomes will be compared primarily between the combined GLP-1RA + MHT and the GLP-1RA only regimen. The third arm (MHT only) will allow exploring mechanistic effects of MHT-mediated restoration of E2 levels on glucose and energy homeostasis and to assess benefits of combined GLP-1RA + MHT, compared to MHT alone, on haemostatic biomarkers.
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Change in HbA1C
timeFrame: 12 Weeks
Secondary outcomes:
measure: Change in postprandial plasma glucose exposure during the OGTT (AUC plasma glucose concentration)
timeFrame: 12 Weeks
measure: Change in average sensor glucose levels
timeFrame: 12 Weeks
measure: Change in time with sensor glucose in tight target range [3.9-7.8 mmol/L]
timeFrame: 12 Weeks
measure: Change in fasting plasma glucose levels
timeFrame: 12 Weeks
measure: Change in body weight
timeFrame: 12 Weeks
measure: Change in body fat percentage
timeFrame: 12 Weeks
measure: Change in non-HDL cholesterol
timeFrame: 12 Weeks
measure: Change in systolic blood pressure
timeFrame: 12 Weeks
measure: Change in liver fat (controlled attenuation parameter)
timeFrame: 12 Weeks
measure: Change in whole-body insulin sensitivity
timeFrame: 12 Weeks
measure: Change in quality of life
timeFrame: 12 Weeks
measure: Change in postmenopausal symptoms burden
timeFrame: 12 Weeks
measure: Change in frequency of vasomotor symptoms
timeFrame: 12 Weeks
measure: Change in intensity of vasomotor symptoms
timeFrame: 12 Weeks
Other outcomes:
measure: Change in incretin effect
timeFrame: 12 Weeks
measure: Change in gastric emptying
timeFrame: 12 Weeks
measure: Change in glucose rate of appearance
timeFrame: 12 Weeks
measure: Change in beta-cell function
timeFrame: 12 Weeks
measure: Change in beta-cell glucose responsivity
timeFrame: 12 Weeks
measure: Change in GLP-1 secretion
timeFrame: 12 Weeks
measure: Change in beta-cell GLP-1 sensitivity
timeFrame: 12 Weeks
measure: Change in GLP-1 potentiation of insulin secretion
timeFrame: 12 Weeks
measure: Change in production ("hepatic") insulin sensitivity
timeFrame: 12 Weeks
measure: Change in disposal ("peripheral") insulin sensitivity
timeFrame: 12 Weeks
measure: Change in energy intake
timeFrame: 12 Weeks
measure: Change in resting energy expenditure
timeFrame: 12 Weeks
measure: Change in total energy expenditure
timeFrame: 12 Weeks
measure: Change in meal frequency
timeFrame: 12 Weeks
measure: Change in diet composition
timeFrame: 12 Weeks
Locations:
city: Bern
country: Switzerland
facility: University Hospital Bern
Study officials:
affiliation: Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital
name: Prof. Dr. med. et Dr. phil.Lia Bally
role: PRINCIPAL_INVESTIGATOR
References: