The aim of this study is to detail the (mechanisms underlying the) actions of the DPP-4 inhibitor linagliptin on the renal system in patients with type 2 diabetes mellitus.

Based on preclinical and small-sized studies in non-diabetic individuals, incretin-based therapies, i.e. glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase-4 inhibitors (DPP-4i), may hold promise in preventing the onset and progression of diabetic kidney disease. However, the potential renoprotective effects of these agents, that are believed to be effectuated "beyond glucose control", have not been sufficiently detailed in human diabetes.

Therefore, the present study aims to explore the mechanistic and clinical effects of DPP-4i on fasting and postprandial renal physiology and biomarkers in patients with type 2 diabetes.

Forty-eight patients with type 2 diabetes will undergo an eight week intervention with linagliptin or glimepiride in order to assess changes in the outcome parameters.

Inclusion Criteria:

• Patients with type 2 diabetes (HbA1c: 6.5-9.0% DCCT or 48-75 mmol/mol IFCC)
• Metformin monotherapy; using a stable dose for at least 3 months prior to inclusion
• Both genders (females must be post-menopausal)
• Caucasian
• Age: 35-75 years
• Body Mass Index: >25 kg/m2
• All patients with previously diagnosed hypertension should use a RAS-interfering agent (angiotensin converting enzyme inhibitor/angiotensin II receptor blocker) for at least 3 months

Exclusion Criteria:

• Current / chronic use of the following medication: thiazolidinediones, insulin, glucocorticoids, immune suppressants, antimicrobial agents or chemotherapeutics. Subjects on diuretics will only be excluded when these drugs (e.g. hydrochlorothiazide) cannot be stopped for the duration of the study
• Chronic use of NSAIDs will not be allowed, unless used as incidental medication (1-2 tablets) for non-chronic indications. However, no such drugs can be taken within a time-frame of 2 weeks prior to renal-testing
• Pregnancy
• Frequent occurrence of (confirmed) hypoglycemia (plasma glucose <3.9 mmol/L)
• Estimated Glomerular Filtration Rate < 60 mL/min/1.73m2 (determined by the Modification of Diet in Renal Disease (MDRD) study equation)
• Current urinary tract infection and active nephritis
• Recent (<6 months) history of cardiovascular disease, including: acute coronary syndrome, chronic heart failure (New York Heart Association grade II-IV), stroke, transient ischemic neurologic disorder
• Complaints compatible with or established gastroparesis and/or neurogenic bladder
• Active liver disease
• History of or actual pancreatic disease
• History of or actual malignancy (except for basal cell carcinoma)
• History of or actual severe mental disease
• Substance abuse (alcohol: defined as >4 units/day; smoking/nicotine: defined as daily smoking/use)
• Allergy to any of the agents used in the study
• Inability to understand the study protocol or give informed consent