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

NCT02914691 | Completed Phase 4 DMC

• 1 other identifier: 2015-000335-32
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Type 2 Diabetes; Diabetic Nephropathy

Keywords

Type 2 diabetes; Diabetic Nephropathy; Proteomics; Albuminuria; SGLT2 inhibitor

Outcome Measures

Primary Outcomes (1)

• 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

Study Arms (2)

Active

ACTIVE COMPARATOR

Dapagliflozin 10 mg once daily tablet treatment

Drug: Dapagliflozine 10 mg once daily tablet treatment

Placebo

PLACEBO COMPARATOR

Identical once daily tablet treatment

Drug: Placebo identical once daily tablet treatment

Interventions

Dapagliflozine 10 mg once daily tablet treatment DRUG

Active

Placebo identical once daily tablet treatment DRUG

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Peter Rossing: lead

Study Sites (1)

Steno Diabetes Center

Gentofte Municipality, 2820, Denmark

Location

Related Publications (3)

• Larsen EL, Andersen A, Kjaer LK, Eickhoff MK, Frimodt-Moller M, Persson F, Rossing P, Lykkesfeldt J, Knop FK, Vilsboll T, Rungby J, Poulsen HE. Effects of two- and twelve-weeks sodium-glucose cotransporter 2 inhibition on DNA and RNA oxidation: two randomized, placebo-controlled trials. Free Radic Res. 2023 Feb;57(2):140-151. doi: 10.1080/10715762.2023.2213820. Epub 2023 May 19.

  PMID: 37171199 DERIVED

• Curovic VR, Eickhoff MK, Ronkko T, Frimodt-Moller M, Hansen TW, Mischak H, Rossing P, Ahluwalia TS, Persson F. Dapagliflozin Improves the Urinary Proteomic Kidney-Risk Classifier CKD273 in Type 2 Diabetes with Albuminuria: A Randomized Clinical Trial. Diabetes Care. 2022 Nov 1;45(11):2662-2668. doi: 10.2337/dc22-1157.

  PMID: 35998283 DERIVED

• 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.

  PMID: 32340841 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Diabetic Nephropathies; Albuminuria

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Complications; Proteinuria; Urination Disorders; Urological Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor, MD, DMSc

Study Record Dates

• First Submitted: September 9, 2016
• First Posted: September 26, 2016
• Study Start: August 1, 2015
• Primary Completion: July 5, 2017
• Study Completion: July 5, 2017
• Last Updated: September 10, 2018

Record last verified: 2018-09

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)