The PRE-D Trial: Effect of Dapagliflozin, Metformin and Physical Activity in Pre-diabetes

Study Overview
=================
Brief Summary
-----------------
The overall objective is to compare the short-term (3 months) effectiveness of three glucose-lowering interventions (dapagliflozin, metformin and physical activity) on glucose variability, body composition, and cardiometabolic risk factors in overweight or obese individuals with pre-diabetes (HbA1c 5.7-6.4% / 39-47 mmol/mol).

Detailed Description
-----------------
Different medical therapies and lifestyle modification for the prevention of type 2 diabetes have yet to be compared head-to-head in individuals with pre-diabetes. This research project will compare different glucose-lowering interventions in overweight and obese individuals with HbA1c levels in the pre-diabetic range.

Official Title
-----------------
Effect of Dapagliflozin, Metformin and Physical Activity on Glucose Variability, Body Composition and Cardiovascular Risk in Pre-diabetes

Conditions
-----------------
Prediabetic State, Obesity

Intervention / Treatment
-----------------
* Drug: Dapagliflozin
* Drug: Metformin
* Behavioral: Exercise


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: HbA1c: from ≥5.7% (39 mmol/mol) to ≤6.4% (47 mmol/mol) Age: from ≥30 to ≤70 years of age BMI ≥25 kg/m2 Exclusion Criteria: Uncontrolled medical issues including but not limited to cardiovascular pulmonary, rheumatologic, hematologic, oncologic, infectious, gastrointestinal or psychiatric disease; diabetes or other endocrine disease; immunosuppression; Current treatment with hormones which affect glucose metabolism; Current treatment with loop diuretics or thiazolidinediones; Current treatment with beta blockers or peroral steroids; Bariatric surgery within the past 2 years; Impaired renal function defined as an estimated GFR<60 ml/min/1.73m2; Neurogenic bladder disorders; Alcohol/drug abuse or in treatment with disulfiram (Antabus) at time of inclusion; Pregnant or lactating women; Fertile women not using birth control agents including oral contraceptives, gestagen injection, subdermal implants, hormonal vaginal ring, transdermal application, or intra-uterine devices; Allergic to one or more of the medications used in the study; Concomitant participation in other intervention study; Unable to understand the informed consent and the study procedures.

Ages Eligible for Study
-----------------
Minimum Age: 30 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin<br>Dapagliflozin, 10 mg per day | Drug: Dapagliflozin<br>* 10 mg per day as monotherapy for 13 weeks<br>* Other names: Forxiga, AstraZeneca;|
| Active Comparator: Metformin<br>Metformin, 2 x 850 mg per day | Drug: Metformin<br>* 2 x 850 mg per day as monotherapy for 13 weeks<br>* Other names: Aurobindo, Orion Pharma;|
| Active Comparator: Exercise<br>Exercise, interval training | Behavioral: Exercise<br>* Interval training, 5 times per week, 30 min per session<br>|
| No Intervention: Control<br>No intervention | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean amplitude of glycaemic excursions (MAGE) as assessed by continuous glucose monitoring |  | Change from baseline to 13 weeks and 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intra-day glycaemic variability as assessed by continuous overall net glycaemic action (CONGA) |  | Change from baseline to 13 weeks and 26 weeks | 
| Daily time spent above different glucose concentrations ( e.g. >6.1 mmol/L, >7.0 mmol/L, >7.8 mmol/L, and >11.1 mmol/L) |  | Change from baseline to 13 weeks and 26 weeks | 
| HbA1c |  | Change from baseline to 13 weeks and 26 weeks | 
| Glucose concentrations during OGTT |  | Change from baseline to 13 weeks and 26 weeks | 
| Insulin secretion as assessed by the insulinogenic index |  | Change from baseline to 13 weeks and 26 weeks | 
| Insulin sensitivity as assessed by the insulin sensitivity index |  | Change from baseline to 13 weeks and 26 weeks | 
| Body weight (kg) |  | Change from baseline to 13 weeks and 26 weeks | 
| Body fat (%) as assessed by DEXA scan |  | Change from baseline to 13 weeks and 26 weeks | 
| Cardiorespiratory fitness as assessed by maximal oxygen uptake (VO2 max) |  | Change from baseline to 13 weeks and 26 weeks | 
| Respiratory exchange ratio (RER) as assessed by indirect calorimetry |  | Change from baseline to 13 weeks and 26 weeks | 
| Basal metabolic rate (BMR) as assessed by indirect calorimetry |  | Change from baseline to 13 weeks and 26 weeks | 
| Time spent sedentary and in moderate-to-vigorous physical activity intensity as assessed by accelerometer |  | Change from baseline to 13 weeks and 26 weeks | 
| Systolic and diastolic blood pressure |  | Change from baseline to 13 weeks and 26 weeks | 
| Plasma lipids |  | Change from baseline to 13 weeks and 26 weeks | 
| Number of self-reported adverse events and side effects |  | Change from baseline to 13 weeks and 26 weeks | 
| Self-rated health and quality of life as assessed by questionnaire |  | Change from baseline to 13 weeks and 26 weeks | 
| Sleep habits as assessed by questionnaire |  | Change from baseline to 13 weeks and 26 weeks | 
| Dietary intake as assessed by a food diary |  | Change from baseline to 13 weeks and 26 weeks | 
| Adherence to the different interventions as assessed by number of tablets returned or number of training passes completed |  | Change from baseline to 13 weeks and 26 weeks | 
| Responsiveness to interventions in individuals with different glucose tolerance status (impaired fasting glycaemia vs. impaired glucose tolerance) |  | Change from baseline to 13 weeks and 26 weeks |