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

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.

Study Overview

• Status: Completed
• Conditions: Diabetic Nephropathy; Type 2 Diabetes
• Intervention / Treatment: Drug: Dapagliflozine 10 mg once daily tablet treatment; Drug: Placebo identical once daily tablet treatment

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Gentofte, Denmark, 2820
    • Steno Diabetes center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active; Dapagliflozin 10 mg once daily tablet treatment	Drug: Dapagliflozine 10 mg once daily tablet treatment
Placebo Comparator: Placebo; Identical once daily tablet treatment	Drug: Placebo identical once daily tablet treatment

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Peter Rossing

Publications and helpful links

General Publications

• Eickhoff MK, Olsen FJ, Frimodt-Moller M, Diaz LJ, Faber J, Jensen MT, Rossing P, Persson F. Effect of dapagliflozin on cardiac function in people with type 2 diabetes and albuminuria - A double blind randomized placebo-controlled crossover trial. J Diabetes Complications. 2020 Jul;34(7):107590. doi: 10.1016/j.jdiacomp.2020.107590. Epub 2020 Apr 18.

Study record dates

Study Major Dates

• Study Start: August 1, 2015
• Primary Completion (Actual): July 5, 2017
• Study Completion (Actual): July 5, 2017

Study Registration Dates

• First Submitted: September 9, 2016
• First Submitted That Met QC Criteria: September 22, 2016
• First Posted (Estimate): September 26, 2016

Study Record Updates

• Last Update Posted (Actual): September 10, 2018
• Last Update Submitted That Met QC Criteria: September 6, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: Type 2 diabetes; Proteomics; Albuminuria; SGLT2 inhibitor; Diabetic Nephropathy
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Urologic Diseases; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 2; Kidney Diseases; Diabetic Nephropathies
• Other Study ID Numbers: 2015-000335-32

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No