Hypoglycemia, Type 2 Diabetes
Conditions
Keywords
diabetes, hypoglycemia, glycemic variability, vildagliptin, glimepiride
Brief summary
The purpose of this study was to compare the effect of a fixed dose combination of vildagliptin plus metformin versus combination therapy of glimepiride plus metformin in glycemic variability in patients with type 2 diabetes who have not achieved adequate control of their disease prior to treatment with metformin monotherapy in optimal doses.
Interventions
DRUGvildagliptin and metformin (combination)
vildagliptin and metformin combination therapy as 50mg/850mg bid or 50mg/1000mg bid
DRUGglimepiride
DRUGMetformin
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * HbA1c between 8%-10.5% in stable metformin dose (\>1500 mg/day), four weeks prior visit 1 Key
Exclusion criteria
* Use of other antidiabetic oral therapy during the last 3 months (sulphonylurea, glitazones, GLP-1 analogues, DPP-4 inhibitors), except metformin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Glycemic Variability Measured by Mean Amplitude of Glucose Excursions (MAGE) | Week 12 | Mean Amplitude of Glycemic Excursions (MAGE) , which determines the average blood glucose excursions either above or below a value of one standard deviation of the average value of glucose in a given day. MAGE is calculated from the data of continuous tissue glucose monitoring obtained during the measurement period. MAGE is calculated with the formula Σ λ / χ if λ\> ν (where λ = changes in blood glucose from peak to nadir, χ = number of valid observations, ν = 1 standard deviation of the mean glucose during a period of 24 hours) from the data of continuous monitoring of the tissue glucose, obtained during the period of measurement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Glycemic Variability Measured by Total Standard Deviation (TSD) | Week 12 | Total standard deviation (TSD) or standard deviation of all values of a given measurement period, which has the advantage of being able to include all measured values on a given time period (even several days) through a common and simple statistical concept. TSD is calculated conventionally with the formula σ = √Σ (Xi - ῦ) 2 / N (where Xi represents each of the values, ῦ represents the population mean and N is the number of observations) from the data of continuous monitoring of tissue glucose obtained during the measurement. |
| Percentage of Patients Who Achieved a Decrease Equal to or Greater Than 0.3% in Value of HbA1c at Week 12 | Screening visit , 12 weeks of treatment | — |
| Change in HbA1c at Week 12 of Treatment in Comparison to HbA1c at Baseline | baseline, 12 weeks of treatment | — |
| Glycemic Variability Measured by Continuous Overlapping Net Glycemic Action (CONGA) | Week 12 | Continuous Overlapping Net Glycemic Action (CONGA) which assesses intra-day glycemic variability by calculating the difference between values at different intervals, adjusted according to requirements with the advantage of being highly reproducible. CONGA is calculated in the conventional way with the formula √tқΣt = t1 (Dt -Ď2) / қ - 1, Ď = tқ Σ Dt t = t1 / қ, Dt = Gt-Gt-m (where қ = Observations with an observation n x 60 minutes, G = glucose measure) from the data of continuous monitoring of tissue glucose obtained during the measurement period. |
| Mean Amplitude of Glycemic Excursions (MAGE) for Patients With Hypoglycemia Incidence After 12 Weeks of Treatment | 12 weeks | MAGE , which determines the average blood glucose excursions either above or below a value of one standard deviation of the average value of glucose in a given day. MAGE is calculated from the data of continuous tissue glucose monitoring obtained during the measurement period. MAGE is calculated with the formula Σ λ / χ if λ\> ν (where λ = changes in blood glucose from peak to nadir, χ = number of valid observations, ν = 1 standard deviation of the mean glucose during a period of 24 hours) from the data of continuous monitoring of the tissue glucose, obtained during the period of measurement. In this endpoint, mean MAGE value is reported for hypo glycemic patients. |
| Number of Patients With Any Adverse Events, Serious Adverse Events and Death | 12 weeks | — |
| Number of Patients With Incidence of Hypoglycemia | 12 weeks | Hypoglycemia defined as Glycemia \< 70 mg/dl |
Countries
Colombia
Participant flow
Pre-assignment details
A total of 9 research centers participated in the study, from which 76 patients were screened for inclusion and exclusion criteria, obtaining 40 patients eligible for randomization
Participants by arm
| Arm | Count |
|---|---|
| Vildagliptin and Metformin Based on basal dose of metformin, administration of vildagliptin/metformin 50 mg/850 mg twice daily (bid) or 50 mg/1000 mg bid for 12 weeks | 20 |
| Glimepiride and Metformin Protocol specified dosage and frequency of glimepiride + metformin for 12 weeks based on basal dose of metformin | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Failure to comply with an eligibility | 0 | 1 |
| Overall Study | Incorrect medication administration | 1 | 0 |
| Overall Study | Ingestion of drugs not allowed in study | 0 | 1 |
| Overall Study | Mis-randomization | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Vildagliptin and Metformin | Glimepiride and Metformin |
|---|---|---|---|
| Age, Continuous | 56.25 Years STANDARD_DEVIATION 10.92 | 56.74 Years STANDARD_DEVIATION 10.58 | 55.70 Years STANDARD_DEVIATION 11.51 |
| Sex: Female, Male Female | 23 Participants | 15 Participants | 8 Participants |
| Sex: Female, Male Male | 17 Participants | 5 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 20 | 13 / 20 |
| serious Total, serious adverse events | 0 / 20 | 1 / 20 |
Outcome results
Primary
Glycemic Variability Measured by Mean Amplitude of Glucose Excursions (MAGE)
Mean Amplitude of Glycemic Excursions (MAGE) , which determines the average blood glucose excursions either above or below a value of one standard deviation of the average value of glucose in a given day. MAGE is calculated from the data of continuous tissue glucose monitoring obtained during the measurement period. MAGE is calculated with the formula Σ λ / χ if λ\> ν (where λ = changes in blood glucose from peak to nadir, χ = number of valid observations, ν = 1 standard deviation of the mean glucose during a period of 24 hours) from the data of continuous monitoring of the tissue glucose, obtained during the period of measurement.
Time frame: Week 12
Population: Analysis set includes all randomized patients excluding the ones who were prematurely withdrawn and the ones who have no data from visit 7 which required for comparison.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vildagliptin and Metformin | Glycemic Variability Measured by Mean Amplitude of Glucose Excursions (MAGE) | 6.68 mg/dL | Standard Deviation 1.48 |
| Glimepiride and Metformin | Glycemic Variability Measured by Mean Amplitude of Glucose Excursions (MAGE) | 6.23 mg/dL | Standard Deviation 1.08 |
p-value: 0.451Wilcoxon (Mann-Whitney)
Secondary
Change in HbA1c at Week 12 of Treatment in Comparison to HbA1c at Baseline
Time frame: baseline, 12 weeks of treatment
Population: Analysis set includes all randomized patients excluding the ones who were prematurely withdrawn and the ones who have confirmed non-concordant data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vildagliptin and Metformin | Change in HbA1c at Week 12 of Treatment in Comparison to HbA1c at Baseline | 1.92 Percentage of glycosylated haemoglobin | Standard Deviation 1.1 |
| Glimepiride and Metformin | Change in HbA1c at Week 12 of Treatment in Comparison to HbA1c at Baseline | 2.28 Percentage of glycosylated haemoglobin | Standard Deviation 0.79 |
Secondary
Glycemic Variability Measured by Continuous Overlapping Net Glycemic Action (CONGA)
Continuous Overlapping Net Glycemic Action (CONGA) which assesses intra-day glycemic variability by calculating the difference between values at different intervals, adjusted according to requirements with the advantage of being highly reproducible. CONGA is calculated in the conventional way with the formula √tқΣt = t1 (Dt -Ď2) / қ - 1, Ď = tқ Σ Dt t = t1 / қ, Dt = Gt-Gt-m (where қ = Observations with an observation n x 60 minutes, G = glucose measure) from the data of continuous monitoring of tissue glucose obtained during the measurement period.
Time frame: Week 12
Population: Analysis set includes all randomized patients excluding the ones who were prematurely withdrawn and the ones who have no data from visit 7 which required for comparison.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vildagliptin and Metformin | Glycemic Variability Measured by Continuous Overlapping Net Glycemic Action (CONGA) | 2.92 mg/dL | Standard Deviation 0.93 |
| Glimepiride and Metformin | Glycemic Variability Measured by Continuous Overlapping Net Glycemic Action (CONGA) | 3.01 mg/dL | Standard Deviation 1.1 |
Secondary
Glycemic Variability Measured by Total Standard Deviation (TSD)
Total standard deviation (TSD) or standard deviation of all values of a given measurement period, which has the advantage of being able to include all measured values on a given time period (even several days) through a common and simple statistical concept. TSD is calculated conventionally with the formula σ = √Σ (Xi - ῦ) 2 / N (where Xi represents each of the values, ῦ represents the population mean and N is the number of observations) from the data of continuous monitoring of tissue glucose obtained during the measurement.
Time frame: Week 12
Population: Analysis set includes all randomized patients excluding the ones who were prematurely withdrawn and the ones who have no data from visit 7 which required for comparison.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vildagliptin and Metformin | Glycemic Variability Measured by Total Standard Deviation (TSD) | 1.36 mg/dL | Standard Deviation 0.4 |
| Glimepiride and Metformin | Glycemic Variability Measured by Total Standard Deviation (TSD) | 1.40 mg/dL | Standard Deviation 0.42 |
Secondary
Mean Amplitude of Glycemic Excursions (MAGE) for Patients With Hypoglycemia Incidence After 12 Weeks of Treatment
MAGE , which determines the average blood glucose excursions either above or below a value of one standard deviation of the average value of glucose in a given day. MAGE is calculated from the data of continuous tissue glucose monitoring obtained during the measurement period. MAGE is calculated with the formula Σ λ / χ if λ\> ν (where λ = changes in blood glucose from peak to nadir, χ = number of valid observations, ν = 1 standard deviation of the mean glucose during a period of 24 hours) from the data of continuous monitoring of the tissue glucose, obtained during the period of measurement. In this endpoint, mean MAGE value is reported for hypo glycemic patients.
Time frame: 12 weeks
Population: Analysis set includes all randomized patients excluding the ones who were prematurely withdrawn and the ones who have no data from visit 7 which required for comparison and had at least one hypoglycemia event.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vildagliptin and Metformin | Mean Amplitude of Glycemic Excursions (MAGE) for Patients With Hypoglycemia Incidence After 12 Weeks of Treatment | 5.23 mg/dL | — |
| Glimepiride and Metformin | Mean Amplitude of Glycemic Excursions (MAGE) for Patients With Hypoglycemia Incidence After 12 Weeks of Treatment | 5.53 mg/dL | Standard Deviation 0.82 |
Secondary
Number of Patients With Any Adverse Events, Serious Adverse Events and Death
Time frame: 12 weeks
Population: All the randomized patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vildagliptin and Metformin | Number of Patients With Any Adverse Events, Serious Adverse Events and Death | Any adverse events (serious and non-serious) | 9 Patients |
| Vildagliptin and Metformin | Number of Patients With Any Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 0 Patients |
| Vildagliptin and Metformin | Number of Patients With Any Adverse Events, Serious Adverse Events and Death | Death | 0 Patients |
| Glimepiride and Metformin | Number of Patients With Any Adverse Events, Serious Adverse Events and Death | Any adverse events (serious and non-serious) | 13 Patients |
| Glimepiride and Metformin | Number of Patients With Any Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 1 Patients |
| Glimepiride and Metformin | Number of Patients With Any Adverse Events, Serious Adverse Events and Death | Death | 0 Patients |
Secondary
Number of Patients With Incidence of Hypoglycemia
Hypoglycemia defined as Glycemia \< 70 mg/dl
Time frame: 12 weeks
Population: Analysis set includes all randomized patients excluding the ones who were prematurely withdrawn and the ones who have no data from visit 7 which required for comparison.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vildagliptin and Metformin | Number of Patients With Incidence of Hypoglycemia | 1 Patients |
| Glimepiride and Metformin | Number of Patients With Incidence of Hypoglycemia | 4 Patients |
Secondary
Percentage of Patients Who Achieved a Decrease Equal to or Greater Than 0.3% in Value of HbA1c at Week 12
Time frame: Screening visit , 12 weeks of treatment
Population: Analysis set includes all randomized patients excluding the ones who were prematurely withdrawn and the ones who have confirmed non-concordant data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vildagliptin and Metformin | Percentage of Patients Who Achieved a Decrease Equal to or Greater Than 0.3% in Value of HbA1c at Week 12 | 100.0 percentage of patients |
| Glimepiride and Metformin | Percentage of Patients Who Achieved a Decrease Equal to or Greater Than 0.3% in Value of HbA1c at Week 12 | 100.0 percentage of patients |