Clinical trial NCT02106104: Renal Effects of DPP-4 Inhibitor Linagliptin in Type 2 Diabetes
Official title: A Phase 4, Monocenter, Randomized, Double-blind, Comparator-controlled, Parallel-group, Mechanistic Intervention Trial to Assess the Effect of 8-week Treatment With the Dipeptidyl Peptidase-4 Inhibitor (DPP-4i) Linagliptin Versus the Sulfonylurea (SU) Derivative Glimepiride on Renal Physiology and Biomarkers in Metformin-treated Patients With Type 2 Diabetes Mellitus (T2DM)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Type 2 Diabetes
Keywords: Type 2 diabetes mellitus
Diabetic kidney disease
Diabetic nephropathy
Renoprotection
DPP-4 inhibitors
Linagliptin
SU derivatives
Glimepiride
Lead sponsor: Amsterdam UMC, location VUmc
Sponsor class: OTHER
First posted: 2014-04-08
Enrollment: 48
Sex: ALL
Minimum age (years): 35
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Changes from baseline following 8-week treatment with linagliptin vs glimepiride on fasting and postprandial renal hemodynamics, measured as GFR / ERPF (determined by inulin/para-aminohippuric-acid clearance)
timeFrame: 8 weeks
Secondary outcomes:
measure: Renal tubular function
timeFrame: 8 weeks
measure: Renal damage, measured by urine biomarkers
timeFrame: 8 weeks
measure: Blood Pressure and Heart Rate
timeFrame: 8 weeks
Other outcomes:
measure: Body anthropometrics: body weight, height, body mass index, waist circumference
timeFrame: 8 weeks
measure: Body fat content
timeFrame: 8 weeks
measure: Systemic hemodynamic variables (blood pressure, heart rate, stroke volume, cardiac output/-index, total systemic vascular resistance)
timeFrame: 8 weeks
measure: Cardiac autonomic nervous system function
timeFrame: 8 weeks
measure: Microvascular function
timeFrame: 8 weeks
measure: Arterial stiffness
timeFrame: 8 weeks
measure: Glycemic variables
timeFrame: 8 weeks
measure: Lipid spectrum
timeFrame: 8 weeks
measure: DPP4- and ACE activity
timeFrame: 8 weeks
Locations:
city: Amsterdam
country: Netherlands
facility: VU University Medical Center
Study officials:
affiliation: Amsterdam UMC, location VUmc
name: Mark Kramer, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Muskiet MHA, Tonneijck L, Smits MM, Kramer MHH, Ouwens DM, Hartmann B, Holst JJ, Touw DJ, Danser AHJ, Joles JA, van Raalte DH. Effects of DPP-4 Inhibitor Linagliptin Versus Sulfonylurea Glimepiride as Add-on to Metformin on Renal Physiology in Overweight Patients With Type 2 Diabetes (RENALIS): A Randomized, Double-Blind Trial. Diabetes Care. 2020 Nov;43(11):2889-2893. doi: 10.2337/dc20-0902. Epub 2020 Sep 8.