Effect of Dapagliflozin on Insulin Secretion and Insulin Sensitivity in Patients With Prediabetes

Study Overview
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Brief Summary
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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
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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.

Official Title
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Effect of Dapagliflozin on Insulin Secretion and Insulin Sensitivity in Patients With Prediabetes

Conditions
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Prediabetes, Impaired Fasting Glucose, Impaired Glucose Tolerance

Intervention / Treatment
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* Drug: Dapagliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin<br>Dapagliflozin capsules, 10 mg, one per day before breakfast during 12 weeks. | Drug: Dapagliflozin<br>* 10 mg, one per day before breakfast during 12 weeks.<br>* Other names: Forxiga;|
| Placebo Comparator: Placebo<br>Placebo capsules, one per day before breakfast during 12 weeks. | Drug: Placebo<br>* one per day before breakfast during 12 weeks.<br>* Other names: Calcined magnesium;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Fasting Glucose levels at week 12 | 
| 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 | Postprandial Glucose levels at Week 12 | 
| 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 | First Phase of Insulin Secretion at Week 12 | 
| 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 | Total Insulin Secretion at Week 12 | 
| 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 | Insulin Sensitivity at Week 12 | 
| Glycosylated Hemoglobin | Glycosylated hemoglobin will be evaluated by ELISA and the entered values reflect the glycosylated hemoglobin at week 12 | Glycosylated Hemoglobin at Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body Weight | The body weight will be measured with a bioimpedance balance and the entered values reflect the body weight at week 12 | Body Weight at Week 12 | 
| 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 | Body Mass Index at Week 12 | 
| Total Cholesterol | Total cholesterol levels will be evaluated by enzymatic/colorimetric techniques and the entered values reflect the total cholesterol level at week 12 | Total Cholesterol levels at Week 12 | 
| Triglycerides | Triglycerides levels will be evaluated with enzymatic/colorimetric techniques and the entered values reflect the triglycerides level at week 12 | Triglycerides levels at Week 12 | 
| 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 | HDL-c levels at Week 12 | 
| Alanine Aminotransferase (ALT) | ALT levels will be evaluated with enzymatic/colorimetric techniques at week 12 | ALT levels at Week 12 | 
| Aspartate Aminotransferase (AST) | AST levels will be evaluated with enzymatic/colorimetric techniques at week 12 | AST levels at Week 12 | 
| Creatinine | Creatinine levels will be evaluated with enzymatic/colorimetric techniques at week 12 | Creatinine levels at Week 12 | 
| Uric Acid | Uric acid levels will be evaluated with enzymatic/colorimetric techniques at week 12 | Uric Acid levels at Week 12 | 
| Systolic Blood Pressure | Systolic Blood pressure will be measured with a digital sphygmomanometer and the entered values reflect the blood pressure at week 12 | Systolic Blood Pressure at Week 12 | 
| Diastolic Blood Pressure | Systolic Blood pressure will be measured with a digital sphygmomanometer and the entered values reflect the blood pressure at week 12 | Diastolic Blood Pressure at Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prediabetes, Impaired fasting glucose, Hyperglycemia, Impaired glucose tolerance, Glucose intolerance, Dapagliflozin, Sodium glucose cotransporter 2 inhibitor, SGLT2