Effects of Dapagliflozin Treatment on Urinary Proteomic Patterns in Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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Background: SGLT2 inhibitors are the first antiglycaemic drugs with a direct renal action. A part from reducing blood glucose, systemic blood pressure and albuminuria are decreased, while natriuresis is increased. Previous research into urinary peptide patterns (proteomics) has revealed that patients in risk of progressive renal disease display a risk peptide pattern in their urine, ahead of decline in renal function. Furthermore a urinary proteome pattern is related to CVD risk. The long-term impact of dapagliflozin (dapa) treatment on renal parameters is unknown, but long term randomized trials are ongoing. By investigating the impact of dapa treatment on this peptide pattern, it will be determined whether this intervention can improve the urinary proteomic peptide pattern. In addition new knowledge regarding renal processes that the treatment influences is sought. The impact of treatment of urinary and tubular markers of oxidative stress and function (metabolomics) will be assessed. These markers are thought to represent one of several deleterious pathways involved in the pathology of diabetic renal disease, and here the impact dapa treatment will be investigated. Improvement of these markers of oxidative stress may indicate long-term benefit. Objective: The primary objective is to assess the impact of three months of treatment with dapa 10 mg once daily or placebo on renal proteomics pattern and other risk markers of diabetic comorbidity. Design: Double blinded, randomized, placebo-controlled crossover, single center study. Treatment period: 2 x 12 weeks. Patient population: 40 patients with type 2 diabetes recruited from Steno Diabetes Center in accordance with the study in- and exclusion criteria. Intervention: Dapa 10 mg daily vs. placebo. Endpoints: Primary outcome: To evaluate the effect of dapa treatment on urinary proteomic patterns in patients with type 2 diabetes, microalbuminuria and eGFR equal to or above 45 ml/min/1.73m2. Secondary endpoints are the effect of the intervention on other markers for tubular function, inflammation, endothelial dysfunction, microcirculation, kidney function, albuminuria, vasoactive hormones in plasma, and effect on global longitudinal strain as measured by echocardiography. Timeframe: Randomisation planned from June 2015, inclusion over the following 9 months. Last patient is expected to be completed October 2016. Data analysis completed December 2016, presentation autumn 2017 and publication early 2018.

Official Title
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Effects of Dapagliflozin Treatment on Urinary Proteomic Patterns in Patients With Type 2 Diabetes

Conditions
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Type 2 Diabetes, Diabetic Nephropathy

Intervention / Treatment
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* Drug: Dapagliflozine 10 mg once daily tablet treatment
* Drug: Placebo identical once daily tablet treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients >18 years of age with a diagnosis of type 2 diabetes (WHO criteria). Patients must be on current stable antiglycaemic treatment with oral drugs (OAD) or insulin 4 weeks before start of study drug and throughout study duration. Patients must be on stable antihypertensive treatment (must include renin-angiotensin system blocking treatment) 4 weeks before start of study drug and throughout study duration. HbA1c >7.5 % Urinary albumin creatinine ratio (UACR) > 30 mg/g (in ≥2 out 3 morning spot urine collections prior to randomisation). eGFR ≥ 45 ml/min/1.73 m2 Stable RAAS-blocking treatment (more than or equal to 4 weeks prior to visit 0) If not stable at visit 0, screening phase can be prolonged to 4 weeks. Exclusion Criteria: Current treatment with loop diuretics Current treatment with thiazolidinediones Current treatment with dapagliflozin or other SGLT2 inhibitor Ongoing cancer treatment Patients on hypertension treatment who are is not on stable antihypertensive treatment (must include renin-angiotensin system blocking treatment) 4 weeks before start of study drug and throughout study duration Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN Total bilirubin >2.0 mg/dL (34.2 µmol/L) Positive serologic evidence of current infectious liver disease including, Hepatitis B surface antigen and antibody and Hepatitis C virus antibody eGFR: <45 mL/min (calculated by MDRD formula) History of unstable or rapidly progressing renal disease Volume depleted patients. Patients at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics should have careful monitoring of their volume status Recent Cardiovascular Events in a patient: 1. Acute Coronary Syndrome (ACS) within 2 months prior to enrolment 2.Hospitalization for unstable angina or acute myocardial infarction within 2 months prior to enrolment 3. Acute Stroke or TIA within two months prior to enrolment 4. Less than two months post coronary artery revascularization Congestive heart failure defined as New York Heart Association (NYHA) class IV, unstable or acute congestive heart failure. Note: eligible patients with congestive heart failure, especially those who are on diuretic therapy, should have careful monitoring of their volume status throughout the study. Pregnant or breastfeeding patients Patients who, in the judgement of the investigator, may be at risk for dehydration

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active<br>Dapagliflozin 10 mg once daily tablet treatment | Drug: Dapagliflozine 10 mg once daily tablet treatment<br> <br> |
| Placebo Comparator: Placebo<br>Identical once daily tablet treatment | Drug: Placebo identical once daily tablet treatment<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Urinary Peptide Patterns (Proteomics) | Proteomics will be evaluated at week 0, at crossover week 12 (+/- 1 week), and at end study week 24 (+/- 1 week) | Up to 26 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetes, Diabetic Nephropathy, Proteomics, Albuminuria, SGLT2 inhibitor