Steatosis, LiverPhase 4EXENDANCT03007329
Effects of Combined Dapagliflozin and Exenatide Versus Dapagliflozin and Placebo on Ectopic Lipids in Patients With Uncontrolled Type 2 Diabetes Mellitus.
A Phase 4 study testing Exenatide and Dapagliflozin in people with Steatosis, Liver and Type2 Diabetes, run by Medical University of Vienna at 1 site in Austria.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Steatosis, Liver, Type2 Diabetes
- What is being tested?
- Exenatide and Dapagliflozin
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 34 participants
- Where
- 1 siteAustria
- Study dates
- 8 Mar 2017to 16 Jan 2020
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 33Show fewer
- 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)
- Other liver disease including chronic viral hepatitis (B or C), alcohol abuse, hemochromatosis, alpha-1antitrypsin deficiency, autoimmune hepatitis, Wilson's disease, primary sclerosing cholangitis or primary biliary cirrhosis, or liver cirrhosis of any etiology
- malignancy within the last 5 years before randomisation
- medullary thyroid cancer
- family history of multiple endocrine neoplasia syndrome
- Alcohol or drug abuse within the 3 months prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to study procedures or study drug intake
- Presence of any absolute or relative contraindication for the conduct of an MRI investigation, such as cardiac pacemakers, ferromagnetic haemostatic clips in the central nervous system, metallic splinters in the eye, ferromagnetic or electronically operated active devices like automatic cardioverter defibrillators,cochlear implants, insulin pumps and nerve stimulators, prosthetic heart valves etc.
- History of bariatric surgery
- Treatment with anti-obesity drugs (e.g. sibutramine, orlistat) 3 months prior to informed consent or any other treatment at the time of screening (i.e. surgery, aggressive diet regimen, etc.) leading to unstable body weight
- Subjects receiving antihypertensive medication and/or thyroid hormones, the dose(s) of which have not been stable for at least 6 weeks prior to baseline
- Current treatment with systemic steroids at time of informed consent (Treatment with local and inhaled steroids is allowed)
- Use of drugs potentially associated with NAFLD for more than 2 consecutive weeks in the 6 months prior to screening.
- Use of anti-NASH drugs (thiazolidinediones, vitamin E, UDCA, SAM-e, betaine, milk thistle, anti-TNF therapies,) in the 3 months prior to randomization.
- Donation of blood (> 400 mL) during the previous 3 months prior to the screening visit or during the duration of the study
- Participation in another trial with an investigational drug within 30 days prior to informed consent.
- Any subject who is the investigator or any coinvestigator, research assistant, pharmacist, study coordinator, other staff thereof, directly involved in the conduct of the protocol.
- Pre-menopausal women (last menstruation ≤1 year prior to informed consent) who:
- are nursing or pregnant or
- are of child-bearing potential and are not practising an acceptable method of birth control, or do not plan to continue using this method throughout the study and do not agree to submit to periodic pregnancy testing during participation in the trial. Acceptable methods of birth control include tubal ligation, transdermal patch, intra uterine devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives,sexual abstinence,( if acceptable by local authorities) double barrier method and vasectomised partner.
Trial locations and contacts
1 site in 1 country.
Austria1 site
Abt. für Endokrinologie & Stoffwechsel, Univ. Klin f. Innere Medizin III
Vienna, 1090
About this study
Official title: A 24 Week Monocentric Prospective Randomized, Placebo-controlled Trial to Evaluate Efficacy of Combination of Exenatide and Dapagliflozin Compared to Dapagliflozin and Placebo and Its Effects on Hepatic, Myocardial and Pancreatic Fat Distribution in Patients With Uncontrolled Type 2 Diabetes Mellitus.
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.
Read more
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
- Being tested
- Exenatide, Exenatide matching Placebo, Dapagliflozin
- Keywords
- SGLT2 inhibitor, GLP1 agonist, type 2 Diabetes, steatosis of the liver, ectopic lipids, combined therapy
- Medical subject headings
- Fatty Liver, Diabetes Mellitus, Type 2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ExenatideDrug
Exenatide will be combined with Dapagliflozin
Exenatide matching PlaceboDrug
Exenatide matching Placebo will be combined with Dapagliflozin
DapagliflozinDrug
Dapagliflozin, in both arms
| Study group | Role | What they receive |
|---|---|---|
| Dapagliflozin & Exenatide | Active comparator | Dapagliflozin 10mg orally once daily \& Exenatide 2mg subcutaneous once weekly Receives: Drug: Exenatide; Drug: Dapagliflozin |
| Dapagliflozin & Placebo | Placebo comparator | Dapagliflozin 10mg orally once daily \& Exenatide matching Placebo 2mg subcutaneous once weekly Receives: Drug: Exenatide matching Placebo; Drug: Dapagliflozin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: baseline - week 24
Secondary outcomes (11)
change in myocardial lipid content measured with magnetic resonance spectroscopy in %
to investigate the effects on myocardial 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.
Measured: baseline - week 24
change in pancreatic lipid content measured with magnetic resonance spectroscopy in %
to investigate the effects on pancreatic 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.
Measured: baseline - week 24
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
safety and tolerability from baseline to end by number of participants with treatment related AEs and SAEs
Measured: baseline- week 24
Quality of Life questionnaire
change from baseline in quality of live assessed by WHO Well Being Index
Measured: baseline - week 24
change in insulin resistance
change from baseline in insulin resistance assessed by HOMA IR Index
Measured: baseline - week 24
change in insulin sensitivity
change from baseline in insulin sensitivity assessed by OGIS
Measured: baseline - week 24
energy expenditure
change from baseline of energy expenditure assessed by indirect calorimetry
Measured: baseline -week 24
energy intake
change from baseline of energy intake assessed by 3 day eating protocols
Measured: baseline -week 24
blood pressure
To assess the effect of combination therapy with dapagliflozin and exenatide on blood pressure compared to dapagliflozin and placebo.
Measured: baseline - week 24
weight loss
To assess the effect of combination therapy with dapagliflozin and exenatide on weight loss compared to dapagliflozin and placebo.
Measured: baseline - week 24.
change in glomerular filtration rate
change in GFR from baseline
Measured: baseline -week 24
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Jan 2017 (estimated)
- Study start8 Mar 2017
- Primary completion26 Nov 2019
- Study completion16 Jan 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Steatosis, LiverStudies of the same condition, open and under way.
- More trials run by Medical University of ViennaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 34 participants (actual)
Sponsor and investigators
- Lead sponsor
- Medical University of Vienna
- Sponsor type
- University, hospital or other
- Collaborators
- AstraZeneca
- Responsible party
- Principal investigator, Alexandra Kautzky-Willer, Medical University of Vienna
- Investigators
- Alexandra Kautzky-Willer, Prof. Dr., Principal investigator, Dep. of Medicine III, Div. of Endocrinology, Gender Medicine Unit
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03007329
- Sponsor's protocol ID
- ESR-15-10882
- Acronym
- EXENDA
- Status last verified
- Apr 2022
- First submitted
- 22 Dec 2016
- Last updated
- 15 Apr 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
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.
PubMed 33464703
Study at a glance
From the registry record, last updated by the sponsor on 15 Apr 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A 24 Week Monocentric Prospective Randomized, Placebo-controlled Trial to Evaluate Efficacy of Combination of Exenatide and Dapagliflozin Compared to Dapagliflozin and Placebo and Its Effects on Hepatic, Myocardial and Pancreatic Fat Distribution in Patients With Uncontrolled Type 2 Diabetes Mellitus.
- ClinicalTrials.gov ID
- NCT03007329
- Acronym / sponsor ID
- EXENDA / ESR-15-10882
- Conditions
- Steatosis, Liver, Type2 Diabetes
- Keywords
- SGLT2 inhibitor, GLP1 agonist, type 2 Diabetes, steatosis of the liver, ectopic lipids, combined therapy
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 34 participants (actual)
- Lead sponsor
- Medical University of ViennaUniversity, hospital or other
- Collaborators
- AstraZeneca
- Study start
- 8 Mar 2017 (actual)
- Primary completion
- 26 Nov 2019 (actual)
- Study completion
- 16 Jan 2020 (actual)
- First posted
- 2 Jan 2017 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Dapagliflozin & Exenatide | Active comparator | Drug: Exenatide, Drug: DapagliflozinDapagliflozin 10mg orally once daily \& Exenatide 2mg subcutaneous once weekly |
| Dapagliflozin & Placebo | Placebo comparator | Drug: Exenatide matching Placebo, Drug: DapagliflozinDapagliflozin 10mg orally once daily \& Exenatide matching Placebo 2mg subcutaneous once weekly |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- T2DM
- Sex: male and female
- HbA1c >=6.5 and <=11
- Age >=18 and <=75 years
- BMI>=25kg/m2
Key exclusion criteria (33 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ExenatideExenatide will be combined with Dapagliflozin | Drug | Dapagliflozin & Exenatide |
| Exenatide matching PlaceboExenatide matching Placebo will be combined with Dapagliflozin | Drug | Dapagliflozin & Placebo |
| DapagliflozinDapagliflozin, in both arms | Drug | Dapagliflozin & Exenatide, Dapagliflozin & Placebo |
Primary outcome
change in hepatic lipid content measured with magnetic resonance spectroscopy in %
Time frame: baseline - week 24
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.
11 secondary outcomes
change in myocardial lipid content measured with magnetic resonance spectroscopy in %
Time frame: baseline - week 24
change in pancreatic lipid content measured with magnetic resonance spectroscopy in %
Time frame: baseline - week 24
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time frame: baseline- week 24
Quality of Life questionnaire
Time frame: baseline - week 24
change in insulin resistance
Time frame: baseline - week 24
change in insulin sensitivity
Time frame: baseline - week 24
energy expenditure
Time frame: baseline -week 24
energy intake
Time frame: baseline -week 24
blood pressure
Time frame: baseline - week 24
weight loss
Time frame: baseline - week 24.
change in glomerular filtration rate
Time frame: baseline -week 24
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Apr 2022.
- Results publication: PubMed 33464703Harreiter 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alexandra Kautzky-Willer, Prof. Dr. principal investigator
Dep. of Medicine III, Div. of Endocrinology, Gender Medicine Unit
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Exenatide and Dapagliflozin in people with Steatosis, Liver and Type2 Diabetes, run by Medical University of Vienna at 1 site in Austria.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Austria. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
change in hepatic lipid content measured with magnetic resonance spectroscopy in % (time frame: baseline - week 24). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03007329, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Apr 2022.