Clinical trial NCT02695810: The PRE-D Trial: Effect of Dapagliflozin, Metformin and Physical Activity in Pre-diabetes
Official title: Effect of Dapagliflozin, Metformin and Physical Activity on Glucose Variability, Body Composition and Cardiovascular Risk in Pre-diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Prediabetic State
Obesity
Lead sponsor: Steno Diabetes Center Copenhagen
Sponsor class: OTHER
Collaborators: name: The Novo Nordic Foundation
name: Rigshospitalet, Denmark
name: AstraZeneca
name: Bayer
First posted: 2016-03-01
Enrollment: 120
Sex: ALL
Minimum age (years): 30
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

Primary outcomes:
measure: Mean amplitude of glycaemic excursions (MAGE) as assessed by continuous glucose monitoring
timeFrame: Change from baseline to 13 weeks and 26 weeks
Secondary outcomes:
measure: Intra-day glycaemic variability as assessed by continuous overall net glycaemic action (CONGA)
timeFrame: Change from baseline to 13 weeks and 26 weeks
measure: 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)
timeFrame: Change from baseline to 13 weeks and 26 weeks
measure: HbA1c
timeFrame: Change from baseline to 13 weeks and 26 weeks
measure: Glucose concentrations during OGTT
timeFrame: Change from baseline to 13 weeks and 26 weeks
measure: Insulin secretion as assessed by the insulinogenic index
timeFrame: Change from baseline to 13 weeks and 26 weeks
measure: Insulin sensitivity as assessed by the insulin sensitivity index
timeFrame: Change from baseline to 13 weeks and 26 weeks
measure: Body weight (kg)
timeFrame: Change from baseline to 13 weeks and 26 weeks
measure: Body fat (%) as assessed by DEXA scan
timeFrame: Change from baseline to 13 weeks and 26 weeks
measure: Cardiorespiratory fitness as assessed by maximal oxygen uptake (VO2 max)
timeFrame: Change from baseline to 13 weeks and 26 weeks
measure: Respiratory exchange ratio (RER) as assessed by indirect calorimetry
timeFrame: Change from baseline to 13 weeks and 26 weeks
measure: Basal metabolic rate (BMR) as assessed by indirect calorimetry
timeFrame: Change from baseline to 13 weeks and 26 weeks
measure: Time spent sedentary and in moderate-to-vigorous physical activity intensity as assessed by accelerometer
timeFrame: Change from baseline to 13 weeks and 26 weeks
measure: Systolic and diastolic blood pressure
timeFrame: Change from baseline to 13 weeks and 26 weeks
measure: Plasma lipids
timeFrame: Change from baseline to 13 weeks and 26 weeks
measure: Number of self-reported adverse events and side effects
timeFrame: Change from baseline to 13 weeks and 26 weeks
measure: Self-rated health and quality of life as assessed by questionnaire
timeFrame: Change from baseline to 13 weeks and 26 weeks
measure: Sleep habits as assessed by questionnaire
timeFrame: Change from baseline to 13 weeks and 26 weeks
measure: Dietary intake as assessed by a food diary
timeFrame: Change from baseline to 13 weeks and 26 weeks
measure: Adherence to the different interventions as assessed by number of tablets returned or number of training passes completed
timeFrame: Change from baseline to 13 weeks and 26 weeks
measure: Responsiveness to interventions in individuals with different glucose tolerance status (impaired fasting glycaemia vs. impaired glucose tolerance)
timeFrame: Change from baseline to 13 weeks and 26 weeks
Other outcomes:
Locations:
city: Gentofte
country: Denmark
facility: Steno Diabetes Center A/S
Study officials:
affiliation: Steno Diabetes Center Copenhagen
name: Marit E Jørgensen, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Perreault L, Faerch K. Approaching pre-diabetes. J Diabetes Complications. 2014 Mar-Apr;28(2):226-33. doi: 10.1016/j.jdiacomp.2013.10.008. Epub 2013 Oct 28.
citation: Faerch K, Hulman A, Solomon TP. Heterogeneity of Pre-diabetes and Type 2 Diabetes: Implications for Prediction, Prevention and Treatment Responsiveness. Curr Diabetes Rev. 2016;12(1):30-41. doi: 10.2174/1573399811666150416122903.
citation: Faerch K, Vistisen D, Johansen NB, Jorgensen ME. Cardiovascular risk stratification and management in pre-diabetes. Curr Diab Rep. 2014 Jun;14(6):493. doi: 10.1007/s11892-014-0493-1.
citation: Hulman A, Foreman YD, Brouwers MCGJ, Kroon AA, Reesink KD, Dagnelie PC, van der Kallen CJH, Greevenbroek MMJV, Faerch K, Vistisen D, Jorgensen ME, Stehouwer CDA, Witte DR. Towards precision medicine in diabetes? A critical review of glucotypes. PLoS Biol. 2021 Mar 11;19(3):e3000890. doi: 10.1371/journal.pbio.3000890. eCollection 2021 Mar.
citation: Faerch K, Blond MB, Bruhn L, Amadid H, Vistisen D, Clemmensen KKB, Vaino CTR, Pedersen C, Tvermosegaard M, Dejgaard TF, Karstoft K, Ried-Larsen M, Persson F, Jorgensen ME. The effects of dapagliflozin, metformin or exercise on glycaemic variability in overweight or obese individuals with prediabetes (the PRE-D Trial): a multi-arm, randomised, controlled trial. Diabetologia. 2021 Jan;64(1):42-55. doi: 10.1007/s00125-020-05306-1. Epub 2020 Oct 16.
citation: Faerch K, Amadid H, Nielsen LB, Ried-Larsen M, Karstoft K, Persson F, Jorgensen ME. Protocol for a randomised controlled trial of the effect of dapagliflozin, metformin and exercise on glycaemic variability, body composition and cardiovascular risk in prediabetes (the PRE-D Trial). BMJ Open. 2017 Jun 6;7(5):e013802. doi: 10.1136/bmjopen-2016-013802.