Renal Effects of DPP-4 Inhibitor Linagliptin in Type 2 Diabetes

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Linagliptin 5 mg QD (N=24)
* Drug: Glimepiride 1 mg QD (N=24)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Linagliptin 5 mg QD (N=24)<br>Linagliptin 5 mg will be taken orally, once daily for 8 weeks | Drug: Linagliptin 5 mg QD (N=24)<br>* Linagliptin 5 mg will be taken orally, once daily for 8 weeks<br>* Other names: Trajenta;|
| Active Comparator: Glimepiride 1 mg QD (N=24)<br>Glimepiride 1 mg will be taken orally, once daily for 8 weeks | Drug: Glimepiride 1 mg QD (N=24)<br>* Glimepiride 1 mg will be taken orally, once daily for 8 weeks<br>* Other names: Amaryl;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) |  | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal tubular function |  | 8 weeks | 
| Renal damage, measured by urine biomarkers |  | 8 weeks | 
| Blood Pressure and Heart Rate |  | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetes mellitus, Diabetic kidney disease, Diabetic nephropathy, Renoprotection, DPP-4 inhibitors, Linagliptin, SU derivatives, Glimepiride