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

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.

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.

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.