Type 2 Diabetes Mellitus
Conditions
Keywords
Diabetes, Insulin, Glargine, Metformin, Forxiga, Diet, Exercise, Lifestyle
Brief summary
The purpose of the study is to determine whether in patients with early type 2 diabetes, a short-term intensive metabolic intervention comprising Forxiga, metformin, basal insulin glargine and lifestyle approaches will be superior to standard diabetes therapy in achieving sustained diabetes remission.
Detailed description
This is a multicentre, open-label, randomized controlled trial in 152 patients with recently-diagnosed T2DM. Participants will be randomized to 2 treatment groups: (a) a 12-week course of treatment with Forxiga, metformin, insulin glargine and lifestyle therapy, and (b) standard diabetes therapy, and followed for a total of 64 weeks (1 year and 3 months). In all participants with HbA1C\<7.3% at the 12 week visit, glucose-lowering medications will be discontinued and participants will be encouraged to continue with lifestyle modifications and regular glucose monitoring. Participants with HbA1C ≥ 7.3% at this visit or who experience hyperglycemia relapse after stopping drugs will receive standard glycemic management as informed by the current Canadian Diabetes Association clinical practice guidelines.
Interventions
DRUGinsulin glargine
Dose is titrated to achieve fasting normoglycemia
DRUGmetformin
Dose is titrated to 1 g bid or maximal tolerated dose
DRUGForxiga
Dose is titrated to 10 mg po daily or maximal tolerated dose
BEHAVIORALLifestyle therapy
Lifestyle intervention includes individualized dietary and exercise advice and frequent visits for goal reinforcement, behavior modification and problem-solving
Sponsors
AstraZeneca
Population Health Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. men and women 30-80 years of age inclusive; 2. type 2 diabetes mellitus diagnosed by a physician within 8 years prior to patient enrollment; 3. anti-diabetic drug regimen (either drug or dose of drug) unchanged during 8 weeks prior to screening and randomization; 4. HbA1C 6.5-9.5% inclusive on no hypoglycemic agents or HbA1C ≤ 8.0% on up to 2 glucose-lowering agents; 5. body mass index ≥ 23 kg/m2; 6. ability and willingness to perform self-monitoring of capillary blood glucose (SMBG); 7. ability and willingness to self-inject insulin; 8. provision of informed consent.
Exclusion criteria
1. current use of insulin therapy; 2. history of hypoglycemia unawareness, or severe hypoglycemia requiring assistance; 3. history of end-stage renal disease or renal dysfunction as evidenced by eGFR\<60 mL/min/1.73 m2 by MDRD formula; 4. history of lactic acidosis or diabetic ketoacidosis; 5. active liver disease or elevated alanine transferase (ALT) levels ≥ 2.5 times upper limit of normal at the time of enrollment; 6. history of bladder cancer or undiagnosed hematuria; 7. history of breast cancer; 8. history of polycythemia; 9. evidence of volume depletion or hypotension (systolic blood pressure \< 90 mmHg); 10. systolic blood pressure \> 180 mmHg or diastolic blood pressure \> 105 mmHg; 11. diagnosed cardiovascular disease (unless cleared for a moderate intensity exercise program by a specialist) including: 1. any history of acute coronary syndrome, hospitalization for unstable angina, myocardial infarction, or revascularization with coronary artery bypass grafting or percutaneous coronary intervention; 2. other evidence of coronary artery disease; 3. peripheral vascular disease, valvular heart disease, cardiomyopathy, aortic dissection, tachyarrhythmias, bradyarrhythmias, prior stroke or TIA; 4. prior hospitalization for heart failure; or 5. ECG findings concerning for ischemic heart disease (i.e. pathological Q-waves, ST-segment-T-wave abnormalities in contiguous leads, left anterior hemiblock, left bundle branch block, second or third degree atrioventricular block). 12. dependence on oxygen; 13. history of any disease requiring frequent intermittent or continuous systemic glucocorticoid treatment; 14. history of bariatric surgery, or planned bariatric surgery in the next 1.5 years; 15. history of any major illness with a life expectancy of \< 3 years; 16. history of injury or any other condition that significantly limits participant's ability to achieve moderate levels of physical activity; 17. any history of excessive alcohol intake, acute or chronic; 18. currently pregnant, or breastfeeding, or not using a reliable method of birth control for the duration of the trial in all females with childbearing potential; reliable methods of birth control include oral contraceptive (birth control pill), hormonal injection, implant, patch, or vaginal ring, intrauterine device, barrier method (condom and spermicide), tubal ligation, partner vasectomy or abstinence; 19. known hypersensitivity to metformin, Forxiga, or insulin glargine.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving Drug-free Diabetes Remission in the Experimental Group Compared to the Control Group | 24 weeks after randomization | Drug-free diabetes remission is defined as HbA1C \< 6.5 % off glucose-lowering agents for at least 12 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving Drug-free HbA1C < 6.0% | 24 weeks after randomization | Drug-free complete diabetes remission is defined as HbA1C \< 6.0 % off glucose-lowering agents for at least 12 weeks. |
| Number of Participants Achieving Diabetes Relapse Without Overt Hyperglycemia Off Diabetes Drugs | 24 weeks | Diabetes relapse without overt hyperglycemia is defined as HbA1C 6.5-6.9% off glucose-lowering agents for at least 12 weeks. |
| Glycated Hemoglobin (HbA1C) | 12 weeks after randomization | Expressed in Diabetes Control and Complications Trial (DCCT) units |
| Number of Participants Achieving Drug-free Diabetes Remission | 64 weeks after randomization | Drug-free diabetes remission is defined as HbA1C \< 6.5 % off glucose-lowering agents for at least 12 weeks. |
| Percentage of Weight Loss From Baseline | 12 weeks after randomization | (Weight at randomization - weight at 12 weeks)/(weight at randomization) |
| Change in Waist Circumference From Baseline | 12 weeks after randomization | (Waist circumference at 12 weeks - waist circumference at randomization) |
| Number of Participants With Severe Hypoglycemic Episodes | During 64 weeks of follow-up | Severe hypoglycemic episode is defined as an event with clinical symptoms consistent with hypoglycemia in which the participant required the assistance of another person, and one of the following: (i) the event was associated with a documented self-measured or laboratory plasma glucose level \</= 2.0 mmol/L or (ii) the event was associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration. |
| Number of Participants With Non-severe Symptomatic Hypoglycemic Episodes | During 64 weeks of follow-up | Symptomatic hypoglycemic episode is defined as an event with clinical symptoms consistent with hypoglycemia. |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intervention Drug: insulin glargine - sc injection; Drug: metformin, oral administration; Drug: forxiga, oral administration; Behavioral: lifestyle therapy, diet and exercise
insulin glargine: Dose is titrated to achieve fasting normoglycemia
metformin: Dose is titrated to 1 g bid or maximal tolerated dose
Forxiga: Dose is titrated to 10 mg po daily or maximal tolerated dose
Lifestyle therapy: Lifestyle intervention includes individualized dietary and exercise advice and frequent visits for goal reinforcement, behavior modification and problem-solving | 77 |
| Standard Care Standard glycemic care as informed by the current clinical practice guidelines | 77 |
| Total | 154 |
Baseline characteristics
| Characteristic | Intervention | Standard Care | Total |
|---|---|---|---|
| Age, Continuous | 56.8 years STANDARD_DEVIATION 10 | 56.7 years STANDARD_DEVIATION 9.6 | 56.8 years STANDARD_DEVIATION 9.7 |
| Body Mass Index (BMI) | 33.3 kg/m^2 STANDARD_DEVIATION 5.8 | 32.5 kg/m^2 STANDARD_DEVIATION 6 | 32.9 kg/m^2 STANDARD_DEVIATION 5.9 |
| Duration of diabetes | 37.7 months STANDARD_DEVIATION 26.7 | 35.8 months STANDARD_DEVIATION 27.8 | 36.8 months STANDARD_DEVIATION 27.2 |
| Glycated hemoglobin (HbA1C) | 6.7 percentage of glycated hemoglobin STANDARD_DEVIATION 0.6 | 6.7 percentage of glycated hemoglobin STANDARD_DEVIATION 0.7 | 6.7 percentage of glycated hemoglobin STANDARD_DEVIATION 0.6 |
| Race/Ethnicity, Customized Caucasian | 64 Participants | 61 Participants | 125 Participants |
| Race/Ethnicity, Customized Non-Caucasian | 13 Participants | 16 Participants | 29 Participants |
| Region of Enrollment Canada | 77 participants | 77 participants | 154 participants |
| Sex: Female, Male Female | 27 Participants | 27 Participants | 54 Participants |
| Sex: Female, Male Male | 50 Participants | 50 Participants | 100 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 77 | 0 / 77 |
| other Total, other adverse events | 12 / 77 | 10 / 77 |
| serious Total, serious adverse events | 3 / 77 | 0 / 77 |
Outcome results
Primary
Number of Participants Achieving Drug-free Diabetes Remission in the Experimental Group Compared to the Control Group
Drug-free diabetes remission is defined as HbA1C \< 6.5 % off glucose-lowering agents for at least 12 weeks.
Time frame: 24 weeks after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Number of Participants Achieving Drug-free Diabetes Remission in the Experimental Group Compared to the Control Group | 19 Participants |
| Standard Care | Number of Participants Achieving Drug-free Diabetes Remission in the Experimental Group Compared to the Control Group | 13 Participants |
Secondary
Change in Waist Circumference From Baseline
(Waist circumference at 12 weeks - waist circumference at randomization)
Time frame: 12 weeks after randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intervention | Change in Waist Circumference From Baseline | -3.0 cm | Standard Deviation 4.1 |
| Standard Care | Change in Waist Circumference From Baseline | -1.3 cm | Standard Deviation 3.3 |
Secondary
Glycated Hemoglobin (HbA1C)
Expressed in Diabetes Control and Complications Trial (DCCT) units
Time frame: 12 weeks after randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intervention | Glycated Hemoglobin (HbA1C) | 5.9 percentage of glycated hemoglobin | Standard Deviation 0.4 |
| Standard Care | Glycated Hemoglobin (HbA1C) | 6.6 percentage of glycated hemoglobin | Standard Deviation 0.7 |
Secondary
Number of Participants Achieving Diabetes Relapse Without Overt Hyperglycemia Off Diabetes Drugs
Diabetes relapse without overt hyperglycemia is defined as HbA1C 6.5-6.9% off glucose-lowering agents for at least 12 weeks.
Time frame: 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Number of Participants Achieving Diabetes Relapse Without Overt Hyperglycemia Off Diabetes Drugs | 20 Participants |
| Standard Care | Number of Participants Achieving Diabetes Relapse Without Overt Hyperglycemia Off Diabetes Drugs | 9 Participants |
Secondary
Number of Participants Achieving Drug-free Diabetes Remission
Drug-free diabetes remission is defined as HbA1C \< 6.5 % off glucose-lowering agents for at least 12 weeks.
Time frame: 64 weeks after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Number of Participants Achieving Drug-free Diabetes Remission | 11 Participants |
| Standard Care | Number of Participants Achieving Drug-free Diabetes Remission | 6 Participants |
Secondary
Number of Participants Achieving Drug-free HbA1C < 6.0%
Drug-free complete diabetes remission is defined as HbA1C \< 6.0 % off glucose-lowering agents for at least 12 weeks.
Time frame: 24 weeks after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Number of Participants Achieving Drug-free HbA1C < 6.0% | 6 Participants |
| Standard Care | Number of Participants Achieving Drug-free HbA1C < 6.0% | 6 Participants |
Secondary
Number of Participants With Non-severe Symptomatic Hypoglycemic Episodes
Symptomatic hypoglycemic episode is defined as an event with clinical symptoms consistent with hypoglycemia.
Time frame: During 64 weeks of follow-up
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Number of Participants With Non-severe Symptomatic Hypoglycemic Episodes | 34 Participants |
| Standard Care | Number of Participants With Non-severe Symptomatic Hypoglycemic Episodes | 15 Participants |
Secondary
Number of Participants With Severe Hypoglycemic Episodes
Severe hypoglycemic episode is defined as an event with clinical symptoms consistent with hypoglycemia in which the participant required the assistance of another person, and one of the following: (i) the event was associated with a documented self-measured or laboratory plasma glucose level \</= 2.0 mmol/L or (ii) the event was associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration.
Time frame: During 64 weeks of follow-up
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Number of Participants With Severe Hypoglycemic Episodes | 0 Participants |
| Standard Care | Number of Participants With Severe Hypoglycemic Episodes | 0 Participants |
Secondary
Percentage of Weight Loss From Baseline
(Weight at randomization - weight at 12 weeks)/(weight at randomization)
Time frame: 12 weeks after randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intervention | Percentage of Weight Loss From Baseline | 2.9 percentage of weight loss | Standard Deviation 3.2 |
| Standard Care | Percentage of Weight Loss From Baseline | 1.0 percentage of weight loss | Standard Deviation 2.5 |