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

Sponsor

Medical University of Vienna (Other)

Overall Status

Completed

CT.gov ID

NCT03007329

Collaborator

AstraZeneca (Industry)

Enrollment

Location

Arms

34.3

Actual Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Steatosis, Liver Type2 Diabetes	Drug: Exenatide Drug: Exenatide matching Placebo Drug: Dapagliflozin	Phase 4

Study Design

Study Type:

Interventional

Actual Enrollment :

34 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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.

Actual Study Start Date :

Mar 8, 2017

Actual Primary Completion Date :

Nov 26, 2019

Actual Study Completion Date :

Jan 16, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Dapagliflozin & Exenatide Dapagliflozin 10mg orally once daily & Exenatide 2mg subcutaneous once weekly	Drug: Exenatide Exenatide will be combined with Dapagliflozin Drug: Dapagliflozin Dapagliflozin, in both arms
Placebo Comparator: Dapagliflozin & Placebo Dapagliflozin 10mg orally once daily & Exenatide matching Placebo 2mg subcutaneous once weekly	Drug: Exenatide matching Placebo Exenatide matching Placebo will be combined with Dapagliflozin Drug: Dapagliflozin Dapagliflozin, in both arms

Arm

Intervention/Treatment

Active Comparator: Dapagliflozin & Exenatide

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

Drug: Exenatide

Exenatide will be combined with Dapagliflozin

Drug: Dapagliflozin

Dapagliflozin, in both arms

Placebo Comparator: Dapagliflozin & Placebo

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

Drug: Exenatide matching Placebo

Exenatide matching Placebo will be combined with Dapagliflozin

Drug: Dapagliflozin

Dapagliflozin, in both arms

Outcome Measures

Primary Outcome Measures

change in hepatic lipid content measured with magnetic resonance spectroscopy in % [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.

Secondary Outcome Measures

change in myocardial lipid content measured with magnetic resonance spectroscopy in % [baseline - week 24]
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.
change in pancreatic lipid content measured with magnetic resonance spectroscopy in % [baseline - week 24]
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.
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [baseline- week 24]
safety and tolerability from baseline to end by number of participants with treatment related AEs and SAEs
Quality of Life questionnaire [baseline - week 24]
change from baseline in quality of live assessed by WHO Well Being Index
change in insulin resistance [baseline - week 24]
change from baseline in insulin resistance assessed by HOMA IR Index
change in insulin sensitivity [baseline - week 24]
change from baseline in insulin sensitivity assessed by OGIS
energy expenditure [baseline -week 24]
change from baseline of energy expenditure assessed by indirect calorimetry
energy intake [baseline -week 24]
change from baseline of energy intake assessed by 3 day eating protocols
blood pressure [baseline - week 24]
To assess the effect of combination therapy with dapagliflozin and exenatide on blood pressure compared to dapagliflozin and placebo.
weight loss [baseline - week 24.]
To assess the effect of combination therapy with dapagliflozin and exenatide on weight loss compared to dapagliflozin and placebo.
change in glomerular filtration rate [baseline -week 24]
change in GFR from baseline

Other Outcome Measures

weight [baseline - week 24]
change in weight from baseline
hip circumference [baseline - week 24]
change in hip circumference from baseline
waist circumference [baseline - week 24]
change in waist circumference from baseline
fasting glucose [baseline - week 24]
change in fasting plasma glucose from baseline
HbA1c reduction >= 0.5% [baseline - week 24]
% of patient with HbA1c reduction of more than 0.5%
weight reduction >= 5% [baseline - week 24]
% of patient with weight reduction of more than 5%
change in triglycerides [baseline - week 24]
change in triglycerides from baseline
change in cholesterol [baseline - week 24]
change in cholesterol from baseline

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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.

Exclusion Criteria:

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)
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.