Tubular Markers in Response to Saxagliptin Therapy

A New Clinical Utility for Tubular Markers to Identify Kidney Responders to Saxagliptin Treatment in Patients With Diabetic Nephropathy

the study aims to investigate whether treatment with saxagliptin would induce beneficial changes in renal NGAL and L-FABP biomarkers and if they would be used as a tool to identify patients' categories with a particular renal response to DPP-4inhibition. Secondly, to find an association between NGAL and L-FABP, and the relevant renal parameters for both baseline values and rate of changes across defined time points.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Saxagliptin 5mg

Detailed Description

Diabetic kidney disease (DKD) is considered a substantial cause of end-stage kidney disease (ESKD) worldwide. Incorporation of renoprotective options during interventions to prevent the development of DKD and attenuation of its progression; is of the utmost importance. Incretin-based therapies, specifically dipeptidyl peptidase 4 (DPP-4) inhibitors exhibited albuminuria lowering potential beyond their antihyperglycemic effects. Saxagliptin, a potent selective DPP-4 inhibitor which has been used as monotherapy or in combination with antidiabetics, has demonstrated great renal efficiency on both experimental and clinical scale .

Although albumin excretion rate (AER) is a powerful predictor of kidney function deterioration and progressive renal dysfunction, it is primarily a marker of glomerular damage and it has some drawbacks. For example; some patients may follow a non-albuminuric pathway to kidney impairment, others do not progress to macroalbuminuria but remain at microalbuminuria or even regress to normoalbuminuria. Thus, more sensitive and specific renal biomarkers than AER will be valuable in predicting early kidney injury and the progression of diabetic renal damage.

Besides glomerular damage, tubulointerstitial dysfunction largely contributes to the pathology of diabetic nephropathy. Neutrophil gelatinase-associated lipocalin (NGAL) and liver type fatty acid binding protein (L-FABP) are apparent as excellent biomarkers of tubular damage and are earlier predictors of acute kidney injury relative to microalbuminuria. NGAL is produced by neutrophils, highly expressed in tubular epithelium and released from tubular cells following damage . L-FABP is expressed in the proximal tubules and secreted into urine upon tubulointerstitial damage. Clinical significance of these biomarkers lies in their emergence in normoalbuminuric patients and their association with increased albuminuria and progression to ESRD with sustained high urinary markers' levels.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 4

Contacts and Locations

Study Locations

• Egypt
  • Al Qāhirah Al Jadīdah, Egypt, 0004
    • Faculty of Pharmacy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• T2 DM,
• prevalent albuminuria (30-3000mg/g),
• controlled hypertension (defined as blood pressure <140/90 mm Hg) on a selected angiotensin receptor blocker, olmesartan 20mg/day for at least 4 weeks before intervention.

Exclusion Criteria:

• type 1 diabetes,
• poorly controlled hypertension (140-160/90-100 mm Hg),
• pancreatitis,
• malignancies
• albuminuria more than 3000mg/g.
• cardiovascular diseases (acute myocardial infarction, cerebrovascular disease in the past 6months,
• End Stage Renal Disease (ESRD) on chronic dialysis, renal transplant, a serum creatinine >6.0 mg/dL, or estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: saxagliptin; patients received 5 mg daily ( 2.5 mg daily dose was given to patients with an eGFR of <50 mL/min/1.73 m2	Drug: Saxagliptin 5mg; Patients would be assigned to saxagliptin (Onglyza® AstraZeneca Pharmaceuticals LP, Indiana, USA), either received a dose of 5 mg or 2.5 mg daily if patients had eGFR <50 mL/min/1.73 m2; Other Names: Onglyza
No Intervention: control; patients received the antihyperglycemic medication(s) such as metformin and/or sulphonyl ureas or insulin with no added gliptins,

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
to measure renal effect of saxagliptin on tubular markers	the rate of change of uNGAL and u LFABP markers would be estimated across the two time points after saxagliptin treatment .	3 months
to measure effect of saxagliptin on renal on albuminuria	the rate of change of UACR would be measured across the two time points after saxagliptin treatment	3 months
to classify renal responders to saxagliptin using tubular markers	patients would be classified into high risk and low risk patients according to their marker levels	3 months

Collaborators and Investigators

• Sponsor: Beni-Suef University
• Investigators: Study Chair: Ahmed A Elberry, prof, Clinical Pharmacology Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt

Publications and helpful links

Helpful Links

• Urinary Proteomics as a Tool to Identify Kidney Responders to Dipeptidyl Peptidase-4 Inhibition: A Hypothesis-Generating Analysis from the MARLINA-T2D Trial

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2019
• Primary Completion (Actual): March 1, 2020
• Study Completion (Actual): April 1, 2020

Study Registration Dates

• First Submitted: August 13, 2020
• First Submitted That Met QC Criteria: August 18, 2020
• First Posted (Actual): August 20, 2020

Study Record Updates

• Last Update Posted (Actual): August 20, 2020
• Last Update Submitted That Met QC Criteria: August 18, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: saxagliptin; uNGAL; u L-FABP; DKD
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Saxagliptin
• Other Study ID Numbers: tubular markers

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No