Menopause, Type 2 Diabetes
Conditions
Keywords
Diabetes, Menopause, Menopausal Hormone Therapy, Womens Health, Randomized Controlled Trial, GLP-1 receptor agonist
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.
Interventions
DRUGGLP-1 Receptor Agonist
Wegovy®
Estradot® and Utrogestan®\* (in women with intact uterus\*)
Sponsors
Lia Bally
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
Switzerland
Contacts
PRINCIPAL_INVESTIGATORProf. Dr. med. et Dr. phil.Lia Bally
Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital
Outcome results
None listed