Type 2 Diabetes
Conditions
Keywords
dapagliflozin, glycemic variability, MAGE, DIABETES MELLITUS
Brief summary
This study will compare the effect of Dapagliflozin added to Metformin vs Metformin alone on blood sugar fluctuations of adults with a recent diagnosis of Type 2 Diabetes (T2D). The duration of the protocol will be 12 weeks. Continuous glucose monitoring will be measured before and at the end of the intervention. The questions this protocol will answer include: * Is there a difference in blood sugar fluctuations when Dapagliflozin is added to Metformin compared with Metformin alone in adults with type 2 Diabetes? * Does Dapagliflozin added to Metformin improve blood glucose control in patients with type 2 Diabetes?
Detailed description
This is an open-label randomized clinical trial aimed to compare the effect of Dapagliflozin added to Metformin vs Metformin alone on glycemic variability of adults with a recent diagnosis of type 2 Diabetes. The central hypothesis is that the addition of Dapagliflozin will lead to a statistically significant improvement in GV parameters compared to Metformin alone. A total of 88 adults aged 18-70 years with T2DM and HbA1c between 7.5% and 12% while on a stable dose of Metformin 2000 mg/day will be enrolled. Participants will be randomized in a 1:1 ratio to one of two treatment arms for a duration of 12 weeks. The primary objective is to compare the change from baseline to end-of-treatment in key glycemic variability indices derived from continuous glucose monitoring (CGM) (Mean Amplitude Glucose Excursions -MAGE, Time in Range), changes in HbA1c, fasting blood glucose, lipid profile, BMI, blood pressure, among others.
Interventions
DIAGNOSTIC_TESTContinuous glucose monitoring
Subjects enrolled will be randomized 1:1 to either receive a daily dosage of dapagliflozin 10 mg and 2000 mg metformin for 12 weeks or 2000 mg metformin. Patients who do not tolerate metformin at 2000mg dose will be downtitrated to 1500 mg daily. In case patients do not tolerate 1500 mg daily, they will be excluded. Both groups will be monitored for 7 days using either iPro™ CGM system (Medtronic, Northridge, CA) or Dexcom G6 CGM (Dexcom Inc, San Diego, CA). Basal continuous glucose monitoring will start at week 1 (first visit), and removed at day 7 and final continuous glucose monitoring will start at week 11 and removed 7 days after (final visit).
Sponsors
AstraZeneca
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Evaluation of efficacy between Dapagliflozin with Metformin (Intervention) vs Metformin alone (Standard of care)
Eligibility
Sex/Gender
ALL
Age
18 Years to 77 Years
Healthy volunteers
No
Inclusion criteria
* Subjects \> 18-77 years-old * Both Male and female * Hba1c ≥ 7.5 % and ≤12% * BMI \> 25 and \<45 kg/m2 * Type 2 diabetes diagnosis, drug-naive
Exclusion criteria
* Hba1c \> 12% * Creatinine clearance CKD-EPI: \< 60 mL/min * LADA or Type 1 diabetes * Gestational diabetes * Clinically significant disease like: hepatic, hematological, oncological, psychiatric or rheumatic disease. * Symptoms of marked uncontrolled diabetes: (marked poliuria or polidipsia + 10% weight loss prior the last 3 months enrollement) * Known hypersensitivity to dapagliflozin or any of the excipients of the product * eGFR persistently \<45 mL/min/1.73 m2 * Unstable or rapidly progressing renal disease * Patients with severe hepatic impairment (Child-Pugh class C) * Any major CV event/Vascular Disease within 3 months prior to signing the consent at enrollment, as assessed by the investigator * For women only - currently pregnant (confirmed with positive pregnancy test) or breast-feeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ΔTriglycerides mg/dL | 12 weeks | It is defined as the difference in triglycerides plasma concentration before and at the end of intervention (W12-W0) |
| ΔHbA1c | 12 weeks | Difference between serum HbA1c before treatment (W0) and at the end of intervention (W12) expressed in percentage. |
| ΔMAGE | 12 weeks | ● Calculation of Mean Amplitude of Glucose Excursion (MAGE): * In the first step, all local maximum/minimum values are determined. * The next step is an evaluation of maximum/minimum pairs against the standard deviation (SD). * If the difference from minimum to maximum is greater than the SD, this variation from the mean measurement is retained. * If the local maximum/minimum is less than 1 SD, it is excluded from further calculations. * These channels are retained and summed to achieve the MAGE |
| Δweight | 12 weeks | The difference between weight before the treatment period (W0) and the end of the intervention is calculated and expressed as delta for results interpretation. |
| ΔTIR %Target 70-180 mg/dL | 12 weeks | Time in range is defined as the percentage of time that the patient's blood glucose is between 70-180 mg/dL. |
| Δinsulin | 12 weeks | Delta insulin is defined as the difference in insulin plasma concentration before treatment (W0) and at the end of the intervention (W12). |
| Δsystolic Blood Pressure | 12 weeks | It is defined as the difference in systolic blood pressure before treatment (W0) and after the end of intervention (W12) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ΔUric Acid | 12 weeks | It is defined as the difference in plasma uric acid concentration before and at the end of intervention (W12-W0) |
Countries
Mexico
Participant flow
Recruitment details
Patient recruitment began in October 2019 and was interrupted due to the SARS-COV-2 pandemic in March 2020. Nevertheless, patients who were already enrolled were followed up. Recruitment was normally restarted in March 2021; one of the inclusion criteria was adjusted, allowing HbA1c \<13.0%, prior limit \<12.0%. The last patient was recruited on December 6th, 2021.The complete study was concluded on March 2021.
Pre-assignment details
Treatment: subjects who met the pre-randomization period and tolerated treatment were randomized 1:1 to receive either DAPA 10 mg/day + MET 2000 mg/day or MET 2000 mg/day for 12 weeks. Of the total of 264 patients surveyed, a sample of 88 met the inclusion criteria and none of the exclusion criteria randomization DAPA+MET n=42 and MET n= 46
Participants by arm
| Arm | Count |
|---|---|
| DAPAGLIFLOZIN 10 mg/Day + METFORMIN 2000 mg/Day for 12 Weeks Subjects enrolled will be randomized 1:1 to either receive a daily dosage of 10 mg dapagliflozin and 2000 mg metformin for 12 weeks
Continuous glucose monitoring: Subjects enrolled will be randomized 1:1 to either receive a daily dosage of dapagliflozin 10 mg and 2000 mg metformin for 12 weeks (n=18) or 2000 mg metformin (n=18). Patients who do not tolerate metformin at 2000mg dose will be downtitrated to 1500 mg daily. In case patients do not tolerate 1500 mg daily, they will be excluded.
Both groups will be monitored for 7 days using either iPro™ CGM system (Medtronic, Northridge, CA) or Dexcom G6 CGM (Dexcom Inc, San Diego, CA). Basal continuous glucose monitoring will start at week 1 (first visit), and removed at day 7 and final continuous glucose monitoring will start at week 11 and removed 7 days after (final visit). | 42 |
| METFORMIN 2000 mg/Day for 12 Weeks Subjects enrolled will be randomized 1:1 to either receive a daily dosage of 2000 mg metformin for 12 weeks
Continuous glucose monitoring: Subjects enrolled will be randomized 1:1 to either receive a daily dosage of dapagliflozin 10 mg and 2000 mg metformin for 12 weeks (n=18) or 2000 mg metformin (n=18). Patients who do not tolerate metformin at 2000mg dose will be downtitrated to 1500 mg daily. In case patients do not tolerate 1500 mg daily, they will be excluded.
Both groups will be monitored for 7 days using either iPro™ CGM system (Medtronic, Northridge, CA) or Dexcom G6 CGM (Dexcom Inc, San Diego, CA). Basal continuous glucose monitoring will start at week 1 (first visit), and removed at day 7 and final continuous glucose monitoring will start at week 11 and removed 7 days after (final visit). | 46 |
| Total | 88 |
Baseline characteristics
| Characteristic | DAPAGLIFLOZIN 10 mg/Day + METFORMIN 2000 mg/Day for 12 Weeks | METFORMIN 2000 mg/Day for 12 Weeks | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 42 Participants | 46 Participants | 88 Participants |
| Age, Continuous | 53.7 years STANDARD_DEVIATION 8.6 | 50.9 years STANDARD_DEVIATION 11.8 | 52 years STANDARD_DEVIATION 10 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 42 Participants | 46 Participants | 88 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| HbA1c% | 9.2 % STANDARD_DEVIATION 1.6 | 9.4 % STANDARD_DEVIATION 1.3 | 9.3 % STANDARD_DEVIATION 1.4 |
| insulin µU/mL | 12.2 µU/mL STANDARD_DEVIATION 13.3 | 10.9 µU/mL STANDARD_DEVIATION 6.6 | 11 µU/mL STANDARD_DEVIATION 9 |
| MAGE mmol/L | 4.3 mmol/L STANDARD_DEVIATION 1.2 | 4.1 mmol/L STANDARD_DEVIATION 1.5 | 4.2 mmol/L STANDARD_DEVIATION 1.3 |
| Region of Enrollment Mexico | 42 Participants | 46 Participants | 88 Participants |
| SBP mm/Hg | 136.1 mm/Hg STANDARD_DEVIATION 21.8 | 130.8 mm/Hg STANDARD_DEVIATION 16.6 | 133 mm/Hg STANDARD_DEVIATION 18 |
| Sex: Female, Male Female | 22 Participants | 23 Participants | 45 Participants |
| Sex: Female, Male Male | 20 Participants | 23 Participants | 43 Participants |
| TIR %target 70-180 mg/dL | 55.5 % | 82.7 % | 69.1 % |
| triglycerides mg/dL | 193 mg/dL | 185.5 mg/dL | 190 mg/dL |
| uric acid mg/dL | 5.7 mg/dL STANDARD_DEVIATION 1.3 | 5.4 mg/dL STANDARD_DEVIATION 1.4 | 5.5 mg/dL STANDARD_DEVIATION 1.3 |
| weight kg | 81.3 kg STANDARD_DEVIATION 19.1 | 80.0 kg STANDARD_DEVIATION 13.9 | 80.5 kg STANDARD_DEVIATION 16 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 42 | 0 / 46 |
| other Total, other adverse events | 0 / 42 | 0 / 46 |
| serious Total, serious adverse events | 0 / 42 | 0 / 46 |
Outcome results
Primary
ΔHbA1c
Difference between serum HbA1c before treatment (W0) and at the end of intervention (W12) expressed in percentage.
Time frame: 12 weeks
Population: In the intention to treat analysis (ITT), early T2DM treatment with DAPA+MET (n=42) resulted in significant improvements in several health indicators compared to patients in the MET group (n=46). Results are presented as Δ, which represents the change between W0 and W12 values
| Arm | Measure | Value (MEAN) |
|---|---|---|
| DAPAGLIFLOZIN 10 mg/Day + METFORMIN 2000 mg/Day for 12 Weeks | ΔHbA1c | -1.8 percentage of HbA1c |
| METFORMIN 2000 mg/Day for 12 Weeks | ΔHbA1c | -1.6 percentage of HbA1c |
Primary
Δinsulin
Delta insulin is defined as the difference in insulin plasma concentration before treatment (W0) and at the end of the intervention (W12).
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| DAPAGLIFLOZIN 10 mg/Day + METFORMIN 2000 mg/Day for 12 Weeks | Δinsulin | -2.5 uU/mL |
| METFORMIN 2000 mg/Day for 12 Weeks | Δinsulin | 0.4 uU/mL |
Primary
ΔMAGE
● Calculation of Mean Amplitude of Glucose Excursion (MAGE): * In the first step, all local maximum/minimum values are determined. * The next step is an evaluation of maximum/minimum pairs against the standard deviation (SD). * If the difference from minimum to maximum is greater than the SD, this variation from the mean measurement is retained. * If the local maximum/minimum is less than 1 SD, it is excluded from further calculations. * These channels are retained and summed to achieve the MAGE
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| DAPAGLIFLOZIN 10 mg/Day + METFORMIN 2000 mg/Day for 12 Weeks | ΔMAGE | -0.8 mmol/dL |
| METFORMIN 2000 mg/Day for 12 Weeks | ΔMAGE | 0.0 mmol/dL |
Primary
Δsystolic Blood Pressure
It is defined as the difference in systolic blood pressure before treatment (W0) and after the end of intervention (W12)
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| DAPAGLIFLOZIN 10 mg/Day + METFORMIN 2000 mg/Day for 12 Weeks | Δsystolic Blood Pressure | -2.0 mm/Hg |
| METFORMIN 2000 mg/Day for 12 Weeks | Δsystolic Blood Pressure | 0.0 mm/Hg |
Primary
ΔTIR %Target 70-180 mg/dL
Time in range is defined as the percentage of time that the patient's blood glucose is between 70-180 mg/dL.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| DAPAGLIFLOZIN 10 mg/Day + METFORMIN 2000 mg/Day for 12 Weeks | ΔTIR %Target 70-180 mg/dL | 31.5 percentage of time |
| METFORMIN 2000 mg/Day for 12 Weeks | ΔTIR %Target 70-180 mg/dL | 0.4 percentage of time |
Primary
ΔTriglycerides mg/dL
It is defined as the difference in triglycerides plasma concentration before and at the end of intervention (W12-W0)
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| DAPAGLIFLOZIN 10 mg/Day + METFORMIN 2000 mg/Day for 12 Weeks | ΔTriglycerides mg/dL | -50.5 mg/dL |
| METFORMIN 2000 mg/Day for 12 Weeks | ΔTriglycerides mg/dL | -21.5 mg/dL |
Primary
Δweight
The difference between weight before the treatment period (W0) and the end of the intervention is calculated and expressed as delta for results interpretation.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| DAPAGLIFLOZIN 10 mg/Day + METFORMIN 2000 mg/Day for 12 Weeks | Δweight | -2.7 kg |
| METFORMIN 2000 mg/Day for 12 Weeks | Δweight | -0.7 kg |
Secondary
ΔUric Acid
It is defined as the difference in plasma uric acid concentration before and at the end of intervention (W12-W0)
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| DAPAGLIFLOZIN 10 mg/Day + METFORMIN 2000 mg/Day for 12 Weeks | ΔUric Acid | -0.4 mg/dL |
| METFORMIN 2000 mg/Day for 12 Weeks | ΔUric Acid | 0.0 mg/dL |