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

NCT ID: NCT03983551

Last Updated: 2019-06-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 101 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-03-01
• Study Completion Date: 2018-02-28

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.

Conditions

Type 2 Diabetes Mellitus; Proteinuria

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Dipeptidyl peptidase 4 inhibitors

Vildagliptin 50 milligrams twice daily in addition to metformin 1000 milligrams once daily

Group Type: EXPERIMENTAL

Dipeptidyl Peptidase 4 Inhibitor

Intervention Type: DRUG

Vildagliptin 50 milligrams twice daily in addition to metformin 1000 milligrams once daily

Sulfonylureas

Glimepiride 2 milligrams twice daily in addition to metformin 1000 milligrams once daily

Group Type: ACTIVE_COMPARATOR

Sulfonylurea

Intervention Type: DRUG

Glimepiride 2 milligrams twice daily in addition to metformin 1000 milligrams once daily

Interventions

Dipeptidyl Peptidase 4 Inhibitor

Vildagliptin 50 milligrams twice daily in addition to metformin 1000 milligrams once daily

Intervention Type: DRUG

Sulfonylurea

Glimepiride 2 milligrams twice daily in addition to metformin 1000 milligrams once daily

Intervention Type: DRUG

Other Intervention Names

DPP-4 inhibitor; SU

Eligibility 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

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 95 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Changhua Christian Hospital

OTHER

Sponsor Role: lead

Responsible Party

Po-Chung Cheng

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Shih Te Tu, MD

Role: STUDY_DIRECTOR

Changhua Christian Hospital

References

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.

Reference Type: BACKGROUND

PMID: 25215271 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24461728 (View on PubMed)

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. doi: 10.1111/j.1523-1755.2005.00058.x.

Reference Type: BACKGROUND

PMID: 15610231 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28704915 (View on PubMed)

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Reference Type: BACKGROUND

PMID: 29222369 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24126227 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25415611 (View on PubMed)

Sola D, Rossi L, Schianca GP, Maffioli P, Bigliocca M, Mella R, Corliano 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.

Reference Type: BACKGROUND

PMID: 26322096 (View on PubMed)

Other Identifiers

190512

Identifier Type: -

Identifier Source: org_study_id