| Outcome Measures: |
Primary: Change in HbA1C, 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., 12 Weeks | Secondary: Change in postprandial plasma glucose exposure during the OGTT (AUC plasma glucose concentration), 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., 12 Weeks|Change in average sensor glucose levels, 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)., 12 Weeks|Change in time with sensor glucose in tight target range [3.9-7.8 mmol/L], 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)., 12 Weeks|Change in fasting plasma glucose levels, The change will be quantified as the difference in fasting plasma glucose levels from Baseline (Visit 1a) to Visit 2a (units: mmol/L)., 12 Weeks|Change in body weight, The change from Baseline (Visit 1a) to Visit 2a will be evaluated (units: kg)., 12 Weeks|Change in body fat percentage, 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., 12 Weeks|Change in non-HDL cholesterol, 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., 12 Weeks|Change in systolic blood pressure, The change in systolic blood pressure from Baseline (Visit 1a) to Visit 2a will be evaluated (units: mmHg)., 12 Weeks|Change in liver fat (controlled attenuation parameter), 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., 12 Weeks|Change in whole-body insulin sensitivity, 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., 12 Weeks|Change in quality of life, 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 Weeks|Change in postmenopausal symptoms burden, 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)., 12 Weeks|Change in frequency of vasomotor symptoms, 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., 12 Weeks|Change in intensity of vasomotor symptoms, 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., 12 Weeks | Other: Change in incretin effect, 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., 12 Weeks|Change in gastric emptying, 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., 12 Weeks|Change in glucose rate of appearance, 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., 12 Weeks|Change in beta-cell function, 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., 12 Weeks|Change in beta-cell glucose responsivity, 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., 12 Weeks|Change in GLP-1 secretion, 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., 12 Weeks|Change in beta-cell GLP-1 sensitivity, 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., 12 Weeks|Change in GLP-1 potentiation of insulin secretion, 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., 12 Weeks|Change in production ("hepatic") insulin sensitivity, 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., 12 Weeks|Change in disposal ("peripheral") insulin sensitivity, 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., 12 Weeks|Change in energy intake, 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 Weeks|Change in resting energy expenditure, 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., 12 Weeks|Change in total energy expenditure, 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., 12 Weeks|Change in meal frequency, 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., 12 Weeks|Change in diet composition, 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., 12 Weeks
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