Comparing the Renal Effect of Dipeptidyl-peptidase 4 Inhibitors and Sulfonylureas

Study Overview
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Brief Summary
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Dipeptidyl peptidase 4 (DPP-4) inhibitors and sulfonylureas have been extensively used in the treatment of type 2 diabetes mellitus (T2DM). Although both medications effectively lower plasma glucose levels, differences may exist in their pharmacokinetics and effect on the kidney. In the context of diabetic kidney disease, DPP-4 inhibitors may confer renal protection through several putative mechanisms. In contrast, sulfonylureas are associated with weight gain and cardiac dysfunction, which may adversely influence kidney function. The investigators hypothesize that DPP-4 inhibitors and sulfonylureas may have a different effect on the diabetic kidney. This study compares the effect of DPP-4 inhibitors and sulfonylureas on urinary albumin excretion in patients with newly diagnosed T2DM.

Detailed Description
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Diabetic kidney disease (DKD) occurs in a considerable number of individuals with type 2 diabetes mellitus (T2DM). DKD leads to substantial morbidity and reduces the quality of life in afflicted patients. Chronic hyperglycemia induces proapoptotic signaling pathways in mesangial cells, leading to microvascular injury in the diabetic kidney. Clinical interventions targeting plasma glucose, body weight, and blood pressure have been shown to attenuate the progression of DKD. Dipeptidyl peptidase 4 (DPP-4) inhibitors and sulfonylureas have been extensively used in the treatment of T2DM. Although both medications effectively lower plasma glucose levels, differences may exist in their pharmacokinetics and effect on the kidney. In the context of DKD, DPP-4 inhibitors may confer renal protection through several putative mechanisms. However, whether such renal protection involves the glucose lowering efficacy of DPP-4 inhibitors or additional mechanisms remains controversial. In contrast, currently there is inadequate information concerning the effect of sulfonylureas on the development of DKD. If the glucose lowering effect of DPP-4 inhibitors is a major determinant of renal protection, then sulfonylureas may theoretically offer similar benefit by maintaining euglycemia. However, sulfonylureas are associated with weight gain and cardiac dysfunction, which may adversely influence kidney function. Given that DPP-4 inhibitors and sulfonylureas have different effect on physiologic parameters including body weight and blood pressure, the investigators hypothesize that these medications may have different effects on the diabetic kidney. This study compares the effect of DPP-4 inhibitors and sulfonylureas on urinary albumin excretion in patients with newly diagnosed T2DM. In this study, patients with newly diagnosed T2DM are screened for eligibility. All participants receive 1000 mg of metformin therapy at the beginning of the study. Subsequently, patients are assigned to receive either the DPP-4 inhibitor Vildagliptin 50 mg twice daily or the sulfonylurea Glimepiride 2 mg twice daily. Treatment allocation is made by a committee of endocrinologists to match participants in the treatment groups by age, body weight, serum glycated hemoglobin (HbA1c), urinary albumin-to-creatinine ratio (ACR), and serum creatinine. At the initial clinic visit, participants receive blood tests for serum HbA1c, serum creatinine, serum alanine transferase, and plasma lipid profile after a 12-hour fast. Urine samples will be collected in the morning after a 12-hour fast, and urinary ACR is measured by the turbidimetric method. Laboratory tests for these clinical variables are repeated after 24 weeks of pharmacologic treatment. Participants who loss follow up or withdraw from the study will be assessed by an intention to treat analysis. The change in urinary ACR is defined as the primary outcome measure, whereas changes in serum HbA1c, serum creatinine, body weight, and systolic blood pressure are considered secondary outcome measures.

Official Title
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Comparing the Effect of Dipeptidyl-peptidase 4 Inhibitors and Sulfonylureas on Urinary Albumin Excretion in People With Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus, Proteinuria

Intervention / Treatment
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* Drug: Dipeptidyl Peptidase 4 Inhibitor
* Drug: Sulfonylurea


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients exceeding 20 years of age Patients with newly diagnosed type 2 diabetes mellitus Patients who have yet to receive antidiabetic medications Exclusion Criteria: Patients with non-diabetic kidney disease Patients with congenital kidney abnormalities Patients with end stage renal disease. Patients who have received angiotensin-converting-enzyme inhibitor or angiotensin II receptor blocker

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 95 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dipeptidyl peptidase 4 inhibitors<br>Vildagliptin 50 milligrams twice daily in addition to metformin 1000 milligrams once daily | Drug: Dipeptidyl Peptidase 4 Inhibitor<br>* Vildagliptin 50 milligrams twice daily in addition to metformin 1000 milligrams once daily<br>* Other names: DPP-4 inhibitor;|
| Active Comparator: Sulfonylureas<br>Glimepiride 2 milligrams twice daily in addition to metformin 1000 milligrams once daily | Drug: Sulfonylurea<br>* Glimepiride 2 milligrams twice daily in addition to metformin 1000 milligrams once daily<br>* Other names: SU;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in urinary albumin-to-creatinine ratio | Change in urinary albumin-to-creatinine ratio after pharmacologic treatment | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in serum glycated hemoglobin A1c | Change in serum glycated hemoglobin A1c after pharmacologic treatment | 24 weeks | 
| Change in body weight | Change in body weight after pharmacologic treatment | 24 weeks | 
| Change in serum creatinine | Change in serum creatinine after pharmacologic treatment | 24 weeks | 
| Change in systolic blood pressure | Change in systolic blood pressure after pharmacologic treatment | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetes mellitus, dipeptidyl peptidase 4 inhibitors, sulfonylureas, proteinuria