Antidiabetic Effects of Adding a DPP-4 Inhibitor to Pre-Existing Treatment With an Incretin Mimetic in Patients With T2D

Objectives: To quantify differences in control of glycemia (primary objective) and the secretion of endogenous incretin hormones (secondary objective) comparing sitagliptin or placebo added to pre-existing therapy with liraglutide and metformin

This is a double blind, controlled, cross-over comparison of adding sitagliptin (or placebo) to pre-existing metformin+liraglutide therapy. Patients with type 2 diabetes mellitus (T2DM) on pre-existing treatment with metformin (≥ 1500 mg/d) monotherapy or metformin plus liraglutide (1.2 mg/d) will be studied. Patients on metformin monotherapy will, after screening and randomization, enter a run-in period of 2 weeks with the additional treatment of liraglutide (0.6 mg/d for 1 week followed by 1.2 mg/d for another week). At the end of this 2 weeks therapy, a mixed meal challenge will take place, with the assessment of glucose and hormone responses (insulin, C-peptide, glucagon, GLP-1 \[glucagon-like peptide-1\], GIP (gastric inhibitory peptide) and gastric emptying as measured by 13C (carbon 13)-octanoate breath tests. Prior to the meal tests, liraglutide will be administered at a dose of 1.2 mg per injection, which is the recommended dose for treatment. Sitagliptin will be used at a dose of 100 mg, which is recommended for clinical use.

Eligibility Criteria:
Inclusion Criteria:

* Signed \& dated written informed consent
* Male \& female subjects with a diagnosis of type 2 diabetes mellitus according to ADA criteria at least 4 months prior to screening
* Medical history without major pathology (with the exception of type 2 diabetes) as judged by the investigator
* On a stable regimen of metformin for at least 1 month and liraglutide 1.2 mg for at least 1 week at the time-point of randomisation.
* Age: 25 - 75 years, both inclusive
* Body mass index (BMI): 22 - 40kg/m\^2, both inclusive
* HbA1c ≥ 6.5 and ≤ 8.5% (≥ 7.0 and ≤ 8.5% for patients without previous liraglutide treatment)
* Female must be post-menopausal, surgically sterilized or practicing an effective birth control

Exclusion criteria

* Subjects with type 1 diabetes, maturity onset diabetes of the young (MODY) or secondary forms of diabetes such as due to pancreatitis
* Current or previous treatment with insulin therapy (except for treatment at diabetes' diagnosis, within a clinical trial, for surgical procedures or during an acute illness, and no insulin administration within the 6 months before screening)
* Treatment with any hypoglycaemic medication other than metformin and liraglutide within one month prior to screening
* Known of diabetic gastroparesis and / or prokinetic therapy
* Subjects that underwent surgery of the upper gastrointestinal tract
* Women who are pregnant, intending to become pregnant during the study period, currently lactating females, or women of child-bearing potential not using highly effective, medically approved birth control methods
* Any severe medical or surgical history of conditions likely to confound study assessments or study endpoints, for example but not limited to haemoglobinopathies, inflammatory bowel disease, cystic fibrosis, bariatric surgery and/or any surgery shortening the intestine, history of lactose intolerance, lactose- or glucose-galactose-malabsorption
* A suspicion of medullary thyroid cancer or a multiple endocrine neoplasia
* A personal or family history of medullar thyroid cancer or a multiple endocrine neoplasia
* Serious and/or unstable coronary heart disease (unstable angina, myocardial infarction within the preceding 6 months), congestive heart failure of New York Heart Association Class III or worse (severe limitation of physical activity; physical activity of low intensity resulting in fatigue, palpitation, or dyspnoea), second/third degree heart block, superior vena cava syndrome, uncontrolled hypertension, history of congenital QT-syndrome within family, history of stroke (within the preceding 6 months) or serious peripheral vascular disease
* History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) that is symptomatic or requires treatment (grade 3), left bundle branch block, or asymptomatic sustained ventricular tachycardia are not allowed
* Marked diabetic complications: severe autonomic or sensory neuropathy including previously diagnosed gastroparesis; proliferative retinopathy
* Any respiratory disease leading to respiratory insufficiency and/or depression including but not limited to clinically significant: bronchial asthma, chronic obstructive pulmonary disease, that might impact to the breath test, as judged by the investigator
* Clinically significant vital signs including known bradycardia with pulse rate \< 50/min or 12-lead ECG findings including QTc (corrected QT interval) \> 450 msec for males or QTc \> 470 msec for women
* Clinically significant abnormal haematology, biochemistry, lipids, or urinalysis or coagulation screening tests, as judged by the Investigator
* Moderate or severe renal dysfunction defined as an estimated creatinine clearance (MDRD equation) GFR (glomerular filtration rate) \<50 ml/min.
* Clinical or laboratory evidence of hepatic dysfunction or disease; laboratory evidence defined as any of the following parameters: alkaline phosphatase, ALT , AST or bilirubin \> 3x ULN (upper Limit of normal). Isolated mild rise in bilirubin considered to be due to Gilbert's condition is allowed
* Uncontrolled high blood pressure (DBP (diastolic blood pressure) \> 95 mmHg and/or SBP (systolic blood pressure) \> 160 mmHg), unless clearly documented to be white-coat hypertension
* History of any psychiatric condition that might impair the subject's ability to understand or to comply with the requirements of the study or to provide informed consent
* History of relevant drug and/or food allergies or a history of severe anaphylactic reaction
* Currently active or history of alcohol abuse (defined as an intake of more than 24 units of alcohol per week; one unit of alcohol equals approximately 250 mL of beer, 100 mL of wine or 35 mL of spirits) or drug addiction (including soft drugs like cannabis products)
* Use of concomitant medication which would be likely to interact with metformin, sitagliptin or liraglutide (according to the subject information leaflet). Participation in another study within the 3 months preceding screening or 5-half-lives of drug studied, whichever is longer, prior to study drug administration
* Malignancy within 5 years of study start, except for successfully treated local basal cell carcinomas
* Known to be positive for Hepatitis B surface antigen or Hepatitis C antibodies (or diagnosed with active hepatitis according to local practice)
* Subject who has donated or lost \> 500 mL blood within 3 months prior to screening \& has a Hb \< 14 g/dl at screening
* History of hypersensitivity to the study drug or any of the excipients or to medicinal products with similar chemical structures
* Veins unsuitable for repeated venipuncture