Effects of Combined Dapagliflozin and Exenatide Versus Dapagliflozin and Placebo on Ectopic Lipids in Patients With Uncontrolled Type 2 Diabetes Mellitus.

NCT03007329 | Completed Phase 4

• 1 other identifier: ESR-15-10882
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief Summary

SGLT2 antagonists and GLP1 agonists are used since a relatively short period as second line therapy if indicated and are well tolerated by patients featuring low risk of hypoglycaemia in comparison to insulin or other oral glucose lowering drug. This new treatment options offer an effective modality to lower blood glucose, if first line therapeutics fail. According to national and international guidelines combination of oral glucose lowering drugs is possible in multiple ways, but is currently not recommended for GLP1 agonists and SGLT2 inhibitors yet, as evidence and supporting studies are missing proving efficacy and safety\]. Thus studies under standardized conditions are urgently needed to answer these unsolved questions. First results of a combination of a SGLT2 Inhibitor and a GLP1 agonist demonstrated huge potential regarding glucose and weight reduction and safety issues. However, further studies are necessary to elucidate potential mechanisms of combination therapy with SGLT2 inhibitors and GLP1 agonists and its effect on weight loss, glucose control, effects on incretins and adipokines, as well as further effects on ectopic lipid accumulation in liver and other tissues as myocard or pancreas in humans. As both monotherapies have effects on weight and metabolism, changes in abdominal, subcutaneous, hepatic, myocardial or pancreatic lipid content might be speculated and are focus of interest in this study. Recently GLP1 agonists were shown to have effects on hepatic lipid reduction in humans with diabetes. Hepatic lipid content and steatosis hepatis are widely discussed to have major effects on progression of diabetes and cardiovascular disease. Thus reduction of lipid accumulation in hepatic tissue might have an effect on diabetes progression. Also higher myocardial lipid accumulation is seen in diabetic patients probably partly responsible for higher cardiovascular risk in diabetics. So far results combining these two drug classes show less weight loss as might have been expected using monotherapy, so that further investigation will definitely shed light on combination of therapeutic concepts. Facing a multiple of positive side effects (weight loss, blood pressure lowering, potential protective cardiac effects) using a combination of SGLT2 and GLP1 seems to be a promising therapeutic option in diabetic subjects.

Conditions

Steatosis, Liver; Type2 Diabetes

Keywords

SGLT2 inhibitor; GLP1 agonist; type 2 Diabetes; steatosis of the liver; ectopic lipids; combined therapy

Outcome Measures

Primary Outcomes (1)

• change in hepatic lipid content measured with magnetic resonance spectroscopy in %

  to investigate the effects on hepatic lipid content reduction of combination therapy with dapagliflozin (10mg daily) and exenatide (2mg weekly) compared to dapagliflozin (10mg daily) and placebo given for 24 weeks in patients with type 2 diabetes mellitus and insufficient glycaemic control despite oral therapy.

  baseline - week 24

Secondary Outcomes (11)

• change in myocardial lipid content measured with magnetic resonance spectroscopy in %

  baseline - week 24

• change in pancreatic lipid content measured with magnetic resonance spectroscopy in %

  baseline - week 24

• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  baseline- week 24

• Quality of Life questionnaire

  baseline - week 24

• change in insulin resistance

  baseline - week 24

Other Outcomes (8)

• weight

  baseline - week 24

• hip circumference

  baseline - week 24

• waist circumference

  baseline - week 24

Study Arms (2)

Dapagliflozin & Exenatide

ACTIVE COMPARATOR

Dapagliflozin 10mg orally once daily \& Exenatide 2mg subcutaneous once weekly

Drug: Exenatide; Drug: Dapagliflozin

Dapagliflozin & Placebo

PLACEBO COMPARATOR

Dapagliflozin 10mg orally once daily \& Exenatide matching Placebo 2mg subcutaneous once weekly

Drug: Exenatide matching Placebo; Drug: Dapagliflozin

Interventions

Exenatide DRUG

Exenatide will be combined with Dapagliflozin

Dapagliflozin & Exenatide

Exenatide matching Placebo DRUG

Exenatide matching Placebo will be combined with Dapagliflozin

Dapagliflozin & Placebo

Dapagliflozin DRUG

Dapagliflozin, in both arms

Dapagliflozin & Exenatide; Dapagliflozin & Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• T2DM
• Sex: male and female
• HbA1c \>=6.5 and \<=11
• Age \>=18 and \<=75 years
• BMI\>=25kg/m2
• Metformin\>=1000mg daily, 8 weeks stable dose Please note: Type 2 diabetes mellitus patients treated with less than 1000 mg metformin per day can only be included if the investigator considers the patient to be on the maximum tolerated dose and the investigator has documented the reason why uptitration to 1000 mg was not possible
• able and willing to not change diet and physical activity during enrollment in study
• consent and able to give informed consent.

You may not qualify if:

• other diabetes diagnosis than T2DM
• patients on other antidiabetic medication (Sulfonylurea, Glitazone, insulin for more than 2 weeks (see below), SGLT2 inhibitors, GLP1 agonist, nateglinide, repaglinide, acarbose, DPP4 inhibitors)
• Subjects currently or previously treated with insulin (with the exception of emergency situations in which insulin was given for less than 14 consecutive days, but not within the last 3 months before screening)
• known intolerance against study medication
• Contraindications including hypersensitivity known to metformin according to the local label
• recurrent urinary tract infections
• GFR \< 60
• Liver enzymes above 3 fold normal range
• Bilirubin higher 3 fold normal range
• Any other clinical condition that would jeopardize patients safety while participating in this clinical trial
• disease at screening (other than NAFLD) such as relevant cardiovascular, gastrointestinal, hepatic, neurologic, psychiatric, endocrine (i.e. pancreatic) except T2DM, hematologic, malignant, infection or other major systemic diseases making implementation of the protocol or interpretation of the study results difficult
• history of pancreatitis
• Known autoimmune disease or chronic inflammatory condition
• Myocardial infarction or stroke within 6 months prior to screening
• Blood dyscrasias or any disorders causing haemolysis or unstable Red Blood Cell (e.g.malaria, babesiosis, haemolytic anaemia)

Sponsors & Collaborators

• Medical University of Vienna: lead
• AstraZeneca: collaborator

Study Sites (1)

Abt. für Endokrinologie & Stoffwechsel, Univ. Klin f. Innere Medizin III

Vienna, 1090, Austria

Location

Related Publications (1)

• Harreiter J, Just I, Leutner M, Bastian M, Brath H, Schelkshorn C, Klepochova R, Krssak M, Kautzky-Willer A. Combined exenatide and dapagliflozin has no additive effects on reduction of hepatocellular lipids despite better glycaemic control in patients with type 2 diabetes mellitus treated with metformin: EXENDA, a 24-week, prospective, randomized, placebo-controlled pilot trial. Diabetes Obes Metab. 2021 May;23(5):1129-1139. doi: 10.1111/dom.14319. Epub 2021 Feb 10.

  PMID: 33464703 RESULT

MeSH Terms

Conditions

Fatty Liver; Diabetes Mellitus, Type 2

Interventions

Exenatide; dapagliflozin

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Peptides; Amino Acids, Peptides, and Proteins; Venoms; Complex Mixtures; Toxins, Biological; Biological Factors

Study Officials

• Alexandra Kautzky-Willer, Prof. Dr.

  Dep. of Medicine III, Div. of Endocrinology, Gender Medicine Unit

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr.

Study Record Dates

• First Submitted: December 22, 2016
• First Posted: January 2, 2017
• Study Start: March 8, 2017
• Primary Completion: November 26, 2019
• Study Completion: January 16, 2020
• Last Updated: April 15, 2022

Record last verified: 2022-04

Locations

AU (1)