Impaired Fasting Glucose, Impaired Glucose Tolerance, Prediabetes
Conditions
Keywords
Prediabetes, Impaired fasting glucose, Hyperglycemia, Impaired glucose tolerance, Glucose intolerance, Dapagliflozin, Sodium glucose cotransporter 2 inhibitor, SGLT2
Brief summary
Prediabetes is a term that refers to alterations in glucose homeostasis, including impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or both, involving a higher risk of progression type 2 diabetes mellitus (T2DM). Dapagliflozin is a selective and reversible inhibitor of sodium-glucose type 2 (SGLT-2) co-transporter, which reduces renal glucose reabsorption and promotes the glucose excretion through urine, so that the blood glucose is improved in patients with T2DM. Although this mechanism is independent of insulin, there are evidence of improved secretion and insulin sensitivity, so it is interesting to assess these effects in patients with prediabetes, as potential therapy for treating such disorders and prevent progression to T2DM. The aim of this study is to evaluate the effect of Dapagliflozin on insulin secretion and insulin sensitivity in patients with prediabetes. The investigators hypothesis is that the administration of dapagliflozin improve insulin secretion and insulin sensitivity in patients with prediabetes.
Detailed description
A randomized, double-blind, placebo-controlled clinical trial in 24 patients with a diagnosis of prediabetes in accordance with the American Diabetes Association (ADA) without treatment. They will be assigned randomly two groups of 12 patients each to receive 10 mg of Dapagliflozin (Forxiga, Astra Zeneca) or placebo, one per day before breakfast during 12 weeks. There will be calculated Area Under the Curve of glucose and insulin, total insulin secretion (Insulinogenic index), first-phase of insulin secretion (Stumvoll index) and insulin sensitivity (Matsuda index). This protocol it's already approved by the local ethics committee and written informed consent it's going to be obtained from all volunteers. Statistical analysis will be presented through measures of central tendency and dispersion, average and deviation standard for quantitative variables; frequencies and percentages for variable qualitative. Qualitative variables will be analyzed by X2, will be used for differences inter-group Mann-Whitney U Test and Wilcoxon Test for the within-groups differences. It will be considered statistical significance p ≤0.05. This protocol was approved by a local ethics committee and written informed consent will be obtained from all volunteers.
Interventions
DRUGDapagliflozin
10 mg, one per day before breakfast during 12 weeks.
DRUGPlacebo
one per day before breakfast during 12 weeks.
Sponsors
University of Guadalajara
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Patients both sexes * Age between 30 and 60 years * Diagnosis of prediabetes according ADA criteria (fasting blood glucose levels between 100-126 mg/dl; postprandial blood glucose levels after an oral glucose tolerance test with 75 of oral glucose between 140-199 mg/dl; or glycosylated hemoglobin between 5.7-6.4%) * Informed consent signed
Exclusion criteria
* Women with confirmed or suspected pregnancy * Women under lactation and/or puerperium * Hypersensibility to ingredients of intervention * Physical impossibility for taking pills * Known uncontrolled renal, hepatic, heart or thyroid diseased * Diabetes diagnosis * Previous treatment for glucose * Body Mass Index ≥35 kg/m2 * Triglycerides ≥500 mg/dL * Total cholesterol ≥240 mg/dL * Low density lipoprotein (c-LDL) ≥190 mg/dL * Blood Pressure ≥140/90 mmHg
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Glucose | Fasting Glucose levels at week 12 | The fasting glucose levels will be evaluated with enzymatic/colorimetric techniques and the entered values reflect the fasting glucose level at week 12 |
| Postprandial Glucose | Postprandial Glucose levels at Week 12 | Postprandial glucose will be evaluated after a oral glucose tolerance test with enzymatic/colorimetric techniques and the entered values reflect the insulin sensitivity at week 12 |
| First Phase of Insulin Secretion | First Phase of Insulin Secretion at Week 12 | The first phase of insulin secretion will be calculated with Stumvoll index and the entered values reflect the frst phase of insulin secretion at week 12. Human studies support the critical physiologic role of the first-phase of insulin secretion in the maintenance of postmeal glucose homeostasis. First phase of insulin secretion was estimated using the Stumvoll index (1283+ 1.829 x insulin 30' - 138.7 x glucose 30' + 3.772 x insulin 0'), the entered values reflect the first phase of insulin secretion |
| Total Insulin Secretion | Total Insulin Secretion at Week 12 | Total insulin secretion will be calculated with insulinogenic index and the entered values reflect the total insulin secretion at week 12. The insulinogenic index is a ratio that relates enhancement of circulating insulin to the magnitude of the corresponding glycemic stimulus. Total insulin secretion was calculated with the insulinogenic index (ΔABC insulin/ΔABC glucose), the entered values reflect the total insulin secretion |
| Insulin Sensitivity | Insulin Sensitivity at Week 12 | Insulin sensitivity will be calculated with Matsuda index and the entered values reflect the insulin sensitivity at week 12. Matsuda Index value is used to indicate insulin resistance on diabetes. Insulin sensitivity was calculated with Matsuda index \[10,000 / √glucose 0' x insulin 0') (mean glucose oral glucose tolerance test (OGTT) x mean insulin OGTT)\]. The entered values reflect the insulin sensitivity |
| Glycosylated Hemoglobin | Glycosylated Hemoglobin at Week 12 | Glycosylated hemoglobin will be evaluated by ELISA and the entered values reflect the glycosylated hemoglobin at week 12 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Aspartate Aminotransferase (AST) | AST levels at Week 12 | AST levels will be evaluated with enzymatic/colorimetric techniques at week 12 |
| Creatinine | Creatinine levels at Week 12 | Creatinine levels will be evaluated with enzymatic/colorimetric techniques at week 12 |
| Body Weight | Body Weight at Week 12 | The body weight will be measured with a bioimpedance balance and the entered values reflect the body weight at week 12 |
| Systolic Blood Pressure | Systolic Blood Pressure at Week 12 | Systolic Blood pressure will be measured with a digital sphygmomanometer and the entered values reflect the blood pressure at week 12 |
| Diastolic Blood Pressure | Diastolic Blood Pressure at Week 12 | Systolic Blood pressure will be measured with a digital sphygmomanometer and the entered values reflect the blood pressure at week 12 |
| Uric Acid | Uric Acid levels at Week 12 | Uric acid levels will be evaluated with enzymatic/colorimetric techniques at week 12 |
| Body Mass Index | Body Mass Index at Week 12 | Body Mas Index will be calculated with the Quetelet index formula and the entered values reflect the body mass index at week 12 |
| Total Cholesterol | Total Cholesterol levels at Week 12 | Total cholesterol levels will be evaluated by enzymatic/colorimetric techniques and the entered values reflect the total cholesterol level at week 12 |
| Triglycerides | Triglycerides levels at Week 12 | Triglycerides levels will be evaluated with enzymatic/colorimetric techniques and the entered values reflect the triglycerides level at week 12 |
| High Density Lipoprotein Cholesterol (HDL-c) | HDL-c levels at Week 12 | HDL-c levels will be evaluated with enzymatic/colorimetric techniques and the entered values reflect the c-HDL level at week 12 |
| Alanine Aminotransferase (ALT) | ALT levels at Week 12 | ALT levels will be evaluated with enzymatic/colorimetric techniques at week 12 |
Countries
Mexico
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin Dapagliflozin capsules, 10 mg, one per day before breakfast during 12 weeks.
Dapagliflozin: 10 mg, one per day before breakfast during 12 weeks. | 12 |
| Placebo Placebo capsules, one per day before breakfast during 12 weeks.
Placebo: one per day before breakfast during 12 weeks. | 12 |
| Total | 24 |
Baseline characteristics
| Characteristic | Dapagliflozin | Placebo | 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 | 12 Participants | 12 Participants | 24 Participants |
| Age, Continuous | 51.5 years STANDARD_DEVIATION 6.3 | 46.7 years STANDARD_DEVIATION 9.8 | 49.1 years STANDARD_DEVIATION 8.05 |
| Alanine Aminotransferase (ALT) | 33.3 IU/L STANDARD_DEVIATION 16 | 37.1 IU/L STANDARD_DEVIATION 26.8 | 35.2 IU/L STANDARD_DEVIATION 21.4 |
| Aspartate Aminotransferase (AST) | 36.0 IU/L STANDARD_DEVIATION 8 | 32.7 IU/L STANDARD_DEVIATION 19.6 | 34.4 IU/L STANDARD_DEVIATION 13.8 |
| Body Mass Index | 30.3 kg/m^2 STANDARD_DEVIATION 3.5 | 33.0 kg/m^2 STANDARD_DEVIATION 2.2 | 31.7 kg/m^2 STANDARD_DEVIATION 2.9 |
| Body Weight | 80.8 kg STANDARD_DEVIATION 16.3 | 83.5 kg STANDARD_DEVIATION 8.2 | 82.2 kg STANDARD_DEVIATION 12.3 |
| Creatinine | 0.06 mmol/L STANDARD_DEVIATION 0.01 | 0.07 mmol/L STANDARD_DEVIATION 0.02 | 0.07 mmol/L STANDARD_DEVIATION 0.02 |
| Diastolic Blood Pressure | 78 mmHg STANDARD_DEVIATION 10 | 77 mmHg STANDARD_DEVIATION 11 | 78 mmHg STANDARD_DEVIATION 11 |
| Fasting Glucose | 5.9 mmol/L STANDARD_DEVIATION 0.4 | 6.0 mmol/L STANDARD_DEVIATION 0.4 | 6.0 mmol/L STANDARD_DEVIATION 0.4 |
| First Phase of Insulin Secretion | 1126 index STANDARD_DEVIATION 604 | 1708 index STANDARD_DEVIATION 709 | 1417 index STANDARD_DEVIATION 656.5 |
| Glycosylated Hemoglobin | 5.8 percentage STANDARD_DEVIATION 0.3 | 5.8 percentage STANDARD_DEVIATION 0.5 | 5.8 percentage STANDARD_DEVIATION 0.4 |
| High Density Lipoprotein cholesterol (HDL-c) | 1.6 mmol/L STANDARD_DEVIATION 0.2 | 1.5 mmol/L STANDARD_DEVIATION 0.2 | 1.6 mmol/L STANDARD_DEVIATION 0.2 |
| Insulin Sensitivity | 1.78 index STANDARD_DEVIATION 1.09 | 1.94 index STANDARD_DEVIATION 0.72 | 1.9 index STANDARD_DEVIATION 0.9 |
| Postprandial Glucose | 9.2 mmol/L STANDARD_DEVIATION 1.4 | 9.5 mmol/L STANDARD_DEVIATION 1.4 | 9.4 mmol/L STANDARD_DEVIATION 1.4 |
| Region of Enrollment Mexico | 12 participants | 12 participants | 24 participants |
| Sex: Female, Male Female | 9 Participants | 8 Participants | 17 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 7 Participants |
| Systolic Blood Pressure | 124 mmHg STANDARD_DEVIATION 9 | 126 mmHg STANDARD_DEVIATION 11 | 125 mmHg STANDARD_DEVIATION 10 |
| Total Cholesterol | 5.0 mmol/L STANDARD_DEVIATION 0.9 | 4.7 mmol/L STANDARD_DEVIATION 0.6 | 4.9 mmol/L STANDARD_DEVIATION 0.8 |
| Total Insulin Secretion | 0.69 index STANDARD_DEVIATION 0.31 | 0.49 index STANDARD_DEVIATION 0.17 | 0.6 index STANDARD_DEVIATION 0.2 |
| Triglycerides | 1.5 mmol/L STANDARD_DEVIATION 0.5 | 1.4 mmol/L STANDARD_DEVIATION 0.6 | 1.5 mmol/L STANDARD_DEVIATION 0.6 |
| Uric Acid | 334 μmol/L STANDARD_DEVIATION 70 | 312 μmol/L STANDARD_DEVIATION 101 | 323 μmol/L STANDARD_DEVIATION 85.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 7 / 12 | 6 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
Fasting Glucose
The fasting glucose levels will be evaluated with enzymatic/colorimetric techniques and the entered values reflect the fasting glucose level at week 12
Time frame: Fasting Glucose levels at week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Fasting Glucose | 5.1 mmol/L | Standard Deviation 0.3 |
| Placebo | Fasting Glucose | 5.9 mmol/L | Standard Deviation 0.5 |
p-value: 0.005Wilcoxon (Mann-Whitney)
Primary
First Phase of Insulin Secretion
The first phase of insulin secretion will be calculated with Stumvoll index and the entered values reflect the frst phase of insulin secretion at week 12. Human studies support the critical physiologic role of the first-phase of insulin secretion in the maintenance of postmeal glucose homeostasis. First phase of insulin secretion was estimated using the Stumvoll index (1283+ 1.829 x insulin 30' - 138.7 x glucose 30' + 3.772 x insulin 0'), the entered values reflect the first phase of insulin secretion
Time frame: First Phase of Insulin Secretion at Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | First Phase of Insulin Secretion | 1096 index | Standard Deviation 388 |
| Placebo | First Phase of Insulin Secretion | 1379 index | Standard Deviation 566 |
p-value: 0.878Wilcoxon (Mann-Whitney)
Primary
Glycosylated Hemoglobin
Glycosylated hemoglobin will be evaluated by ELISA and the entered values reflect the glycosylated hemoglobin at week 12
Time frame: Glycosylated Hemoglobin at Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Glycosylated Hemoglobin | 5.7 percentage | Standard Deviation 0.3 |
| Placebo | Glycosylated Hemoglobin | 5.9 percentage | Standard Deviation 0.4 |
p-value: 0.331Wilcoxon (Mann-Whitney)
Primary
Insulin Sensitivity
Insulin sensitivity will be calculated with Matsuda index and the entered values reflect the insulin sensitivity at week 12. Matsuda Index value is used to indicate insulin resistance on diabetes. Insulin sensitivity was calculated with Matsuda index \[10,000 / √glucose 0' x insulin 0') (mean glucose oral glucose tolerance test (OGTT) x mean insulin OGTT)\]. The entered values reflect the insulin sensitivity
Time frame: Insulin Sensitivity at Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Insulin Sensitivity | 2.63 index | Standard Deviation 1.04 |
| Placebo | Insulin Sensitivity | 1.94 index | Standard Deviation 0.71 |
p-value: 0.005Wilcoxon (Mann-Whitney)
Primary
Postprandial Glucose
Postprandial glucose will be evaluated after a oral glucose tolerance test with enzymatic/colorimetric techniques and the entered values reflect the insulin sensitivity at week 12
Time frame: Postprandial Glucose levels at Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Postprandial Glucose | 8.4 mmol/L | Standard Deviation 1.5 |
| Placebo | Postprandial Glucose | 8.7 mmol/L | Standard Deviation 2.7 |
p-value: 0.093Wilcoxon (Mann-Whitney)
Primary
Total Insulin Secretion
Total insulin secretion will be calculated with insulinogenic index and the entered values reflect the total insulin secretion at week 12. The insulinogenic index is a ratio that relates enhancement of circulating insulin to the magnitude of the corresponding glycemic stimulus. Total insulin secretion was calculated with the insulinogenic index (ΔABC insulin/ΔABC glucose), the entered values reflect the total insulin secretion
Time frame: Total Insulin Secretion at Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Total Insulin Secretion | 0.50 index | Standard Deviation 0.18 |
| Placebo | Total Insulin Secretion | 0.67 index | Standard Deviation 0.33 |
p-value: 0.959Wilcoxon (Mann-Whitney)
Secondary
Alanine Aminotransferase (ALT)
ALT levels will be evaluated with enzymatic/colorimetric techniques at week 12
Time frame: ALT levels at Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Alanine Aminotransferase (ALT) | 29.3 IU/L | Standard Deviation 13.6 |
| Placebo | Alanine Aminotransferase (ALT) | 27.7 IU/L | Standard Deviation 14 |
p-value: 0.066Wilcoxon (Mann-Whitney)
Secondary
Aspartate Aminotransferase (AST)
AST levels will be evaluated with enzymatic/colorimetric techniques at week 12
Time frame: AST levels at Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Aspartate Aminotransferase (AST) | 29.3 IU/L | Standard Deviation 13.6 |
| Placebo | Aspartate Aminotransferase (AST) | 27.7 IU/L | Standard Deviation 14 |
p-value: 0.333Wilcoxon (Mann-Whitney)
Secondary
Body Mass Index
Body Mas Index will be calculated with the Quetelet index formula and the entered values reflect the body mass index at week 12
Time frame: Body Mass Index at Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Body Mass Index | 29.2 kg/m^2 | Standard Deviation 3.1 |
| Placebo | Body Mass Index | 32.6 kg/m^2 | Standard Deviation 2.3 |
p-value: 0.005Wilcoxon (Mann-Whitney)
Secondary
Body Weight
The body weight will be measured with a bioimpedance balance and the entered values reflect the body weight at week 12
Time frame: Body Weight at Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Body Weight | 77.8 kg | Standard Deviation 14.9 |
| Placebo | Body Weight | 82.5 kg | Standard Deviation 7.5 |
p-value: 0.005Wilcoxon (Mann-Whitney)
Secondary
Creatinine
Creatinine levels will be evaluated with enzymatic/colorimetric techniques at week 12
Time frame: Creatinine levels at Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Creatinine | 79.6 µmol/L | Standard Deviation 35.4 |
| Placebo | Creatinine | 61.9 µmol/L | Standard Deviation 17.7 |
p-value: 0.859Wilcoxon (Mann-Whitney)
Secondary
Diastolic Blood Pressure
Systolic Blood pressure will be measured with a digital sphygmomanometer and the entered values reflect the blood pressure at week 12
Time frame: Diastolic Blood Pressure at Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Diastolic Blood Pressure | 77 mmHg | Standard Deviation 10 |
| Placebo | Diastolic Blood Pressure | 74 mmHg | Standard Deviation 10 |
p-value: 0.72Wilcoxon (Mann-Whitney)
Secondary
High Density Lipoprotein Cholesterol (HDL-c)
HDL-c levels will be evaluated with enzymatic/colorimetric techniques and the entered values reflect the c-HDL level at week 12
Time frame: HDL-c levels at Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | High Density Lipoprotein Cholesterol (HDL-c) | 1.5 mmol/L | Standard Deviation 0.7 |
| Placebo | High Density Lipoprotein Cholesterol (HDL-c) | 1.6 mmol/L | Standard Deviation 0.2 |
p-value: 0.721Wilcoxon (Mann-Whitney)
Secondary
Systolic Blood Pressure
Systolic Blood pressure will be measured with a digital sphygmomanometer and the entered values reflect the blood pressure at week 12
Time frame: Systolic Blood Pressure at Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Systolic Blood Pressure | 124 mmHg | Standard Deviation 12 |
| Placebo | Systolic Blood Pressure | 123 mmHg | Standard Deviation 12 |
p-value: 0.919Wilcoxon (Mann-Whitney)
Secondary
Total Cholesterol
Total cholesterol levels will be evaluated by enzymatic/colorimetric techniques and the entered values reflect the total cholesterol level at week 12
Time frame: Total Cholesterol levels at Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Total Cholesterol | 4.8 mmol/L | Standard Deviation 0.9 |
| Placebo | Total Cholesterol | 4.7 mmol/L | Standard Deviation 0.8 |
p-value: 0.575Wilcoxon (Mann-Whitney)
Secondary
Triglycerides
Triglycerides levels will be evaluated with enzymatic/colorimetric techniques and the entered values reflect the triglycerides level at week 12
Time frame: Triglycerides levels at Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Triglycerides | 1.5 mmol/L | Standard Deviation 0.7 |
| Placebo | Triglycerides | 1.6 mmol/L | Standard Deviation 0.2 |
p-value: 0.314Wilcoxon (Mann-Whitney)
Secondary
Uric Acid
Uric acid levels will be evaluated with enzymatic/colorimetric techniques at week 12
Time frame: Uric Acid levels at Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Uric Acid | 261.7 µmol/L | Standard Deviation 59.5 |
| Placebo | Uric Acid | 303.4 µmol/L | Standard Deviation 83.3 |
p-value: 0.009Wilcoxon (Mann-Whitney)