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

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.

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Key information

Conditions

Type 2 Diabetes Albuminuria Diabetes Complications Diabetes Mellitus Diabetes Mellitus, Type 2 Diabetic Nephropathies Diabetic Nephropathy Endocrine System Diseases Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Glucose Metabolism Disorders Kidney Diseases Male Urogenital Diseases Metabolic Diseases Nutritional and Metabolic Diseases Pathological Conditions, Signs and Symptoms Proteinuria Signs and Symptoms Urination Disorders Urogenital Diseases Urologic Diseases Urological Manifestations

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Steno Diabetes Center

Gentofte Municipality, 2820, Denmark

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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:

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

Treatment and study plan

Dapagliflozine 10 mg once daily tablet treatment

Drug

Placebo identical once daily tablet treatment

Drug

Primary outcomes

Change in Urinary Peptide Patterns (Proteomics)

Time frame: Up to 26 weeks

Proteomics will be evaluated at week 0, at crossover week 12 (+/- 1 week), and at end study week 24 (+/- 1 week)

Sponsors and collaborators

Lead sponsor

Peter Rossing

Other

Registry information

Acronym: DapKid

Important dates

Study start: 2015
Primary completion: 2017
Study completion: 2017
First posted: Sep 26, 2016
Registry last updated: Sep 10, 2018

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

Published trials that share one or more normalized conditions with this study.

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