Effects of Dapagliflozin 10 mg on Insulin Resistance in Patients With Type 2 Diabetes Mellitus (DERISC)

An 8-week, Single Centre, Randomized, Parallel-group, Double-blind, Placebo Controlled Phase IV Study to Evaluate Dapagliflozin 10 mg Once Daily Effects on Insulin Resistance in Subjects With Type 2 Diabetes Mellitus

This is an 8-week, single centre, randomized, parallel-group, double-blind, placebo-controlled Phase IV study to evaluate the effect of dapagliflozin on tissue specific insulin sensitivity in patients with Type 2 diabetes mellitus

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Dapagliflozin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 4

Contacts and Locations

Study Locations

• Finland
  • Turku, Finland
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Main Inclusion Criteria:

1. Provision of signed informed consent prior to any study specific procedures.
2. Female or male aged 35 to 70 years inclusive with suitable veins for cannulation or repeated venipuncture
3. Type 2 Diabetes mellitus defined as HbA1c of ≥ 6.5% and ≤ 10.5%.
4. Stable (≥ 3 months) T2D treatment with metformin and/or metformin+dipeptidyl peptidase-4 inhibitors (DPP-IV)
5. Body mass index (BMI) ≤ 40 kg/m2.

6. Female subjects must be of non-childbearing potential, meeting at least one of the following criteria:

   1. Hysterectomized females
   2. Postmenopausal women, defined as women who have not had a menstrual period within 1 year

Main Exclusion Criteria:

1. Any condition that is contraindicated with MRI such as, but not limited to, having a pacemaker or claustrophobia.
2. 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.

3. Recent Cardiovascular Events in a patient:

   • Acute Coronary Syndrome (ACS) within 2 months prior to enrolment
   • Hospitalization for unstable angina or acute myocardial infarction within 2 months prior to enrolment
   • Acute Stroke or Transient Ischemic Attack (TIA) within two months prior to enrolment
   • Less than two months post coronary artery revascularization
4. Congestive heart failure defined as New York Heart Association (NYHA) class IV, unstable or acute congestive heart failure.
5. Blood pressure at enrolment: Systolic BP ≥165 mm Hg and/or diastolic BP ≥100 mm Hg
6. Any clinically significant illness, medical or surgical procedure or trauma within 4 weeks of the first administration of the investigational product.
7. On insulin, GLP-1 or other oral antidiabetic drug treatment (metformin or both metformin and DPP-IV allowed) or using other medications known to affect glucose metabolism.

8. Any clinically significant abnormalities in physical examination, Electrocardiography (ECG) or clinical chemistry results as judged by the investigator. The following specific exclusion criteria apply to the selected Clinical Chemistry results:

   1. Creatinine clearance <60mL/min (estimated with Cockroft-Gault formula).
   2. 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.
   3. Total bilirubin (TB) >2.0 mg/dL (34.2 µmol/L).
9. Body weight loss greater than 5% within 3 months prior to Visit 1.
10. Previous PET scan
11. History of or presence of (as found at Visit 1) any clinically significant disease, disorder or condition which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dapagliflozin; Dapagliflozin Once Daily 10 mg	Drug: Dapagliflozin; Dapagliflozin 10 mg Tablets, Oral, Once Daily, 8 weeks; Other Names: Forxiga, Farxiga
Placebo Comparator: Placebo; Matching placebo for Dapagliflozin Once Daily 10 mg	Drug: Placebo; Matching placebo to Dapagliflozin 10 mg Tablets, Oral, Once Daily, 8 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adjusted Change From Baseline in Skeletal Muscle Insulin-stimulated Gluocose Uptake	Adjusted change from baseline in skeletal muscle insulin-stimulated gluocose uptake (umol/min/kg)	From baseline to Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adjusted Change in Adipose Tissue Insulin-stimulated Glucose Uptake	Change in adipose tissue insulin-stimulated glucose uptake assessed by hyperglycemic-euglycemic clamp using F-FDG PET	Baseline to Week 8
Adjusted Change in Liver Insulin-stimulated Glucose Uptake From Baseline to Week 8	Adjusted change in liver insulin-stimulated glucose uptake assessed by hyperglycemic-euglycemic clamp using F-FDG PET	Baseline to Week 8

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Antaros Medical; Bioventure Hub; 43183 Mölndal; Sweden
• Investigators: Principal Investigator: Pirjo Nuutila, MD, PhD, Professor, Turku PET Centre, Turku, Finland

Publications and helpful links

General Publications

• Latva-Rasku A, Honka MJ, Kullberg J, Mononen N, Lehtimaki T, Saltevo J, Kirjavainen AK, Saunavaara V, Iozzo P, Johansson L, Oscarsson J, Hannukainen JC, Nuutila P. The SGLT2 Inhibitor Dapagliflozin Reduces Liver Fat but Does Not Affect Tissue Insulin Sensitivity: A Randomized, Double-Blind, Placebo-Controlled Study With 8-Week Treatment in Type 2 Diabetes Patients. Diabetes Care. 2019 May;42(5):931-937. doi: 10.2337/dc18-1569. Epub 2019 Mar 18.

Study record dates

Study Major Dates

• Study Start (Actual): March 23, 2015
• Primary Completion (Actual): April 28, 2016
• Study Completion (Actual): April 28, 2016

Study Registration Dates

• First Submitted: April 22, 2015
• First Submitted That Met QC Criteria: April 22, 2015
• First Posted (Estimate): April 27, 2015

Study Record Updates

• Last Update Posted (Actual): February 5, 2018
• Last Update Submitted That Met QC Criteria: July 24, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: Insulin resistance; Dapagliflozin; Diabetes Mellitus; Insulin sensitivity; Placebo
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Hyperinsulinism; Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin Resistance; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: D1690C00025; 2014-005377-36 (EudraCT Number)