Impact on Glycemic Variability After Treatment With Dapagliflozin on Type 2 Diabetes Patients

Study Overview
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Brief Summary
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Glycemic variability is refered as swings in glucemic concentration throughout the day, including preprandial and postprandial glucose, and it has been proposed that could be determinant in the development in microvascular complications of type 2 diabetes (Brownlee and Hirsch 2006) SGLT2 inhibitors (SGLT2i) are a novel group of medications for treating type 2 diabetes patients but their effect on glucose variability, and oxidative stress has not been determined as a primary endpoint in clinical trials of type 2 diabetes mellitus patients. The aim of this study is to compare the effect of SGLT2 inhibition on glucose variability, oxidative stress and inflammatory disease biomarkers (VCAM-1) on new onset type 2 DM patients.

Detailed Description
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The aim of this study is to compare the effect of SGLT2 inhibition on glucose variability, oxidative stress and inflammatory disease biomarkers (VCAM-1) on new onset type 2 DM patients. Methods: The investigators will include 36 patients with type 2 diabetes diagnosis with an Hba1c ≥ 7.5% and ≤ 9%, with BMI > 25 and <45 kg/m2, drug-naïve subjects. 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. Patients who do not achieve glycaemic control, another antihyperglycaemic drug can be used. 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), or other available in Mexico. 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). The main variables of interest are going to be in order of importance the delta of change (before and after study entry) of: 1.- glycaemic variability, 2.- change in Hba1c. 3.- change in oxidative stress status, 4. change in VCAM-1, 5.- change in weight, 6.- Blood pressure and 7.- waist circumference; before and after SGLT2i. The expected results are: compared to standard treatment, dapagliflozin arm will have lower glycaemic variability, higher reduction in Hba1c, lower oxidative stress, lower inflammsatory biomarker levels, and lower blood pressure

Official Title
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Impact on Glycaemic Variability, Oxidative Stress and Inflammatory Disease Biomarkers After Treatment With Dapagliflozin as Dual Therapy With Metformin on Mexican Type 2 Diabetes Patients. A Randomized, Open-label Study

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Diagnostic Test: Continuous glucose monitoring


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects > 18-77 years-old Both Male and female Hba1c ≥ 7.5 % and ≤9% BMI > 25 and <45 kg/m2 Type 2 diabetes diagnosis, drug-naïve Exclusion Criteria: Hba1c > 9% 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 enrolment, as assessed by the investigator For women only - currently pregnant (confirmed with positive pregnancy test) or breast-feeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 77 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
Interventional Model Description: dapagliflozin vs standard care
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Daily dosage of dapagliflozin and metformin<br>Subjects enrolled will be randomized 1:1 to either receive a daily dosage of 10 mg dapagliflozin and 2000 mg metformin for 12 weeks | Diagnostic Test: Continuous glucose monitoring<br>* 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).<br>|
| Experimental: Daily dosage of metformin<br>Subjects enrolled will be randomized 1:1 to either receive a daily dosage of 2000 mg metformin for 12 weeks | Diagnostic Test: Continuous glucose monitoring<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Impact of dapagliflozin in glycemic variability | Patients from both groups (dapagliflozin + metformin and metformin) 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) comparing glycemic variability between them. Mean difference of glycaemic variability (MAGE) calculated in mmol/L. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Impact of dapagliflozin in insulin level concentration | Mean difference of insulin serum concentrations represented in μU/mL | 12 weeks | 
| Impact of dapagliflozin in Hba1c | Mean difference of HbA1c represented in % | 12 weeks | 
| Impact of dapagliflozin on patients weight | Mean difference of weight represented in kilograms | 12 weeks | 
| Impact of dapagliflozin in blood pressure | Mean difference of systolic and diastolic blood pressure represented in mmHg | 12 weeks | 
| Impact of dapagliflozin in waist circumference | Mean difference waist measured in centimeters | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dapagliflozin, glycemic variability