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出境医 / 临床实验 / Comparing the Renal Effect of Dipeptidyl-peptidase 4 Inhibitors and Sulfonylureas

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

Study Description
Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Proteinuria Drug: Dipeptidyl Peptidase 4 Inhibitor Drug: Sulfonylurea Phase 4

Detailed Description:

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.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 101 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Comparing the Effect of Dipeptidyl-peptidase 4 Inhibitors and Sulfonylureas on Urinary Albumin Excretion in People With Type 2 Diabetes Mellitus
Actual Study Start Date : March 1, 2016
Actual Primary Completion Date : February 10, 2018
Actual Study Completion Date : February 28, 2018
Arms and Interventions
Arm Intervention/treatment
Experimental: Dipeptidyl peptidase 4 inhibitors
Vildagliptin 50 milligrams twice daily in addition to metformin 1000 milligrams once daily
 Drug: Dipeptidyl Peptidase 4 Inhibitor
Vildagliptin 50 milligrams twice daily in addition to metformin 1000 milligrams once daily
Other Name: DPP-4 inhibitor
Active Comparator: Sulfonylureas
Glimepiride 2 milligrams twice daily in addition to metformin 1000 milligrams once daily
 Drug: Sulfonylurea
Glimepiride 2 milligrams twice daily in addition to metformin 1000 milligrams once daily
Other Name: SU
Outcome Measures
Primary Outcome Measures :
  1. Change in urinary albumin-to-creatinine ratio [ Time Frame: 24 weeks ]
    Change in urinary albumin-to-creatinine ratio after pharmacologic treatment


Secondary Outcome Measures :
  1. Change in serum glycated hemoglobin A1c [ Time Frame: 24 weeks ]
    Change in serum glycated hemoglobin A1c after pharmacologic treatment

  2. Change in body weight [ Time Frame: 24 weeks ]
    Change in body weight after pharmacologic treatment

  3. Change in serum creatinine [ Time Frame: 24 weeks ]
    Change in serum creatinine after pharmacologic treatment

  4. Change in systolic blood pressure [ Time Frame: 24 weeks ]
    Change in systolic blood pressure after pharmacologic treatment


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   20 Years to 95 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations

Sponsors and Collaborators
Changhua Christian Hospital
Investigators
Layout table for investigator information
Study Director: Shih Te Tu, MD Changhua Christian Hospital
Tracking Information
First Submitted Date  ICMJE June 11, 2019
First Posted Date  ICMJE June 12, 2019
Last Update Posted Date June 14, 2019
Actual Study Start Date  ICMJE March 1, 2016
Actual Primary Completion Date February 10, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 11, 2019) 		Change in urinary albumin-to-creatinine ratio [ Time Frame: 24 weeks ]
Change in urinary albumin-to-creatinine ratio after pharmacologic treatment
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 11, 2019)
  • Change in serum glycated hemoglobin A1c [ Time Frame: 24 weeks ]
    Change in serum glycated hemoglobin A1c after pharmacologic treatment
  • Change in body weight [ Time Frame: 24 weeks ]
    Change in body weight after pharmacologic treatment
  • Change in serum creatinine [ Time Frame: 24 weeks ]
    Change in serum creatinine after pharmacologic treatment
  • Change in systolic blood pressure [ Time Frame: 24 weeks ]
    Change in systolic blood pressure after pharmacologic treatment
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Comparing the Renal Effect of Dipeptidyl-peptidase 4 Inhibitors and Sulfonylureas
Official Title  ICMJE Comparing the Effect of Dipeptidyl-peptidase 4 Inhibitors and Sulfonylureas on Urinary Albumin Excretion in People With Type 2 Diabetes Mellitus
Brief Summary

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

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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Type 2 Diabetes Mellitus
  • Proteinuria
Intervention  ICMJE
  • Drug: Dipeptidyl Peptidase 4 Inhibitor
    Vildagliptin 50 milligrams twice daily in addition to metformin 1000 milligrams once daily
    Other Name: DPP-4 inhibitor
  • Drug: Sulfonylurea
    Glimepiride 2 milligrams twice daily in addition to metformin 1000 milligrams once daily
    Other Name: SU
Study Arms  ICMJE
  • Experimental: Dipeptidyl peptidase 4 inhibitors
    Vildagliptin 50 milligrams twice daily in addition to metformin 1000 milligrams once daily
    Intervention: Drug: Dipeptidyl Peptidase 4 Inhibitor
  • Active Comparator: Sulfonylureas
    Glimepiride 2 milligrams twice daily in addition to metformin 1000 milligrams once daily
    Intervention: Drug: Sulfonylurea
Publications *
  • Park CW. Diabetic kidney disease: from epidemiology to clinical perspectives. Diabetes Metab J. 2014 Aug;38(4):252-60. doi: 10.4093/dmj.2014.38.4.252. Review.
  • Stanton RC. Clinical challenges in diagnosis and management of diabetic kidney disease. Am J Kidney Dis. 2014 Feb;63(2 Suppl 2):S3-21. doi: 10.1053/j.ajkd.2013.10.050. Review.
  • Mishra R, Emancipator SN, Kern T, Simonson MS. High glucose evokes an intrinsic proapoptotic signaling pathway in mesangial cells. Kidney Int. 2005 Jan;67(1):82-93.
  • Kim MK. Treatment of diabetic kidney disease: current and future targets. Korean J Intern Med. 2017 Jul;32(4):622-630. doi: 10.3904/kjim.2016.219. Epub 2017 Jun 30. Review.
  • Introduction: Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018 Jan;41(Suppl 1):S1-S2. doi: 10.2337/dc18-Sint01.
  • Davidson JA. The placement of DPP-4 inhibitors in clinical practice recommendations for the treatment of type 2 diabetes. Endocr Pract. 2013 Nov-Dec;19(6):1050-61. doi: 10.4158/EP12303.RA. Review.
  • Makino Y, Fujita Y, Haneda M. Dipeptidyl peptidase-4 inhibitors in progressive kidney disease. Curr Opin Nephrol Hypertens. 2015 Jan;24(1):67-73. doi: 10.1097/MNH.0000000000000080. Review.
  • Sola D, Rossi L, Schianca GP, Maffioli P, Bigliocca M, Mella R, Corlianò F, Fra GP, Bartoli E, Derosa G. Sulfonylureas and their use in clinical practice. Arch Med Sci. 2015 Aug 12;11(4):840-8. doi: 10.5114/aoms.2015.53304. Epub 2015 Aug 11.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 11, 2019) 		101
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE February 28, 2018
Actual Primary Completion Date February 10, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years to 95 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03983551
Other Study ID Numbers  ICMJE 190512
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: All individual participant data that underlie results in a publication.
Supporting Materials: Study Protocol
Time Frame: Starting immediately after publication.
Access Criteria: Available to any interested researcher.
Responsible Party Po-Chung Cheng, Changhua Christian Hospital
Study Sponsor  ICMJE Changhua Christian Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Shih Te Tu, MD Changhua Christian Hospital
PRS Account Changhua Christian Hospital
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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