The INDORSE Study: Inhibition of Dipeptidyl Peptidase IV: Outcomes on Renal Sodium Excretion

Study Overview
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Brief Summary
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Background: Dedicated renal hemodynamic and renal function studies are lacking for DPP-4 inhibitors in patients with Type 2 diabetes; accordingly little is known regarding the mechanisms mediating the renal effects of DPP-4 inhibitors in humans. Objectives: To evaluate the effect of DPP-4 inhibition acutely (single dose) and following short-term therapy (28 days) on renal sodium handling and renal hemodynamics and function in patients with type 2 diabetes and systolic hypertension. Design: double-blind, randomized, placebo-controlled trial, Phase IV. Patient population: 32 patients with Type 2 diabetes, HbA1c (6.5%-9%), with systolic blood pressure ranging from 120-160 mmHg. Intervention: subjects will be randomized (1:1) to either sitagliptin (100 mg daily) or to placebo (1 tablet daily) for 28 days. Endpoints: Fractional excretion of sodium, renal function, and renal hemodynamics.

Detailed Description
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Background: DPP-4 inhibition improves glycemic control, modestly reduces blood pressure and may also reduce albuminuria in patients with Type 2 diabetes; effects which occur without significantly modifying heart rate or body weight. While preclinical studies have demonstrated that DPP-4 inhibition acutely increases urinary sodium excretion in addition to other favorable renal effects (anti-inflammatory, anti-proteinuric), few studies have examined the renal effects of DPP-4 inhibition either acutely or following short-term therapy in humans with type 2 diabetes. Considering the world-wide prevalence of Type 2 diabetes and the increasing use of DPP-4 inhibitors amongst patients, it is important to ascertain potential non-glycemic effects of DPP-4 inhibitors including those within the kidney. Study Objectives: To determine effect(s) of DPP-4 inhibition on tubular sodium handling, renal hemodynamics, and renal function. Study Design: double-blind, randomized, placebo-controlled trial, Phase IV. Study Patients: 32 patients with Type 2 Diabetes and Systolic Hypertension (SBP 120-160 mmHg). Endpoints: Fractional excretion of sodium, renal function (measured GFR), renal hemodynamics (effective renal plasma flow, filtration fraction, renal blood flow, renal vascular resistance), systemic hemodynamics (non-invasive cardiac monitoring), plasma neurohormones, urinary vasoactive mediators, markers of free radical stress.

Official Title
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Effects of DPP-4 Inhibitor Therapy on Renal Sodium Handling and Renal Hemodynamics in Type 2 Diabetes Patients. The INDORSE Study: Inhibition of Dipeptidyl Peptidase IV: Outcomes on Renal Sodium Excretion

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Sitaglitpin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals of 18-70 years of age, with Type 2 Diabetes, with an HbA1c (6.5%-9%), and with a systolic blood pressure (120-160 mmHg). Exclusion Criteria: Individuals with: Type 1 Diabetes, eGFR <50mL/min/1.73m, pregnancy or breast feeding, significant cardiac, pulmonary or liver disease, prior history of pancreatitis, medullary thyroid cancer, multiple endocrine neoplasia syndromes, SBP >161 mmHg, 7) DBP >100 mmHg, alcohol or substance abuse, states of secondary hypertension.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental arm<br>sitagliptin (DPP-4 inhibitor) oral tablet (100 mg); Januvia; administered once daily for 28 days | Drug: Sitaglitpin<br>* Oral DPP-4 inhibitor, 100 mg tablet administered once daily for 28 days<br>* Other names: Januvia;|
| Placebo Comparator: Placebo arm<br>placebo (no medicinal ingredients) oral tablet (100 mg); administered once daily for 28 days | Other: Placebo<br>* Oral tablet (no medicinal ingredients) administered once daily for 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Fractional Excretion of Sodium (FENA) | FENA at 3Hrs post-study drug administration after 1 month compared to FENA at 3Hrs post-study drug administration after 1 dose expressed as percent change, sitagliptin vs. placebo | 3 Hrs post-administration after 1 month and after 1 dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Glomerular Filtration Rate (GFR) | Measured GFR (Inulin Clearance) at 3Hrs post study-drug after 1 month compared to Measured GFR at 3Hrs post-study drug after 1 dose, sitagliptin vs. placebo | 3 Hrs post-administration after 1 month and after 1 dose | 
| Change in Fractional Excretion of Lithium (FELi) | FELi at 3 Hr post-study drug administration after 1 month compared to FELI at 3hrs post-study drug administration after 1 dose, sitagliptin vs. placebo | 3 Hrs post-administration after 1 month and after 1 dose | 
| Change From Baseline in SDF-1alpha^1-67 (Intact) Measured by Immunoaffinity and Tandem Mass Spectrometry | Plasma concentration of SDF-1alpha^1-67 (intact) measured by quantitative mass spectrometry methods after antibody-based affinity enrichment, sitagliptin vs. placebo | 3 Hr vs. baseline after 1 dose | 
| Change From Baseline in SDF-1alpha^3-67 (Truncated) Measured by Tandem Mass Spectrometry With Antibody-based Affinity Enrichment | Plasma concentration of SDF-1alpha^3-67 (intact) measured by quantitative mass spectrometry methods after antibody-based affinity enrichment, sitagliptin vs. placebo | 3Hrs vs baseline after 1 dose | 
| Change in Systolic Blood Pressure (SBP), Non-invasive Cardiac Output Monitoring | SBP by Non-Invasive cardiac output monitoring at 3Hrs post- study drug administration after 1 month compared to SBP by Non-invasive cardiac output monitoring at 3Hrs after 1 dose, sitagliptin vs placebo | 3 Hrs post-administration after 1 month and after 1 dose | 
| Change in Effective Renal Plasma Flow (ERPF) | ERPF (para-aminohippurate clearance) 3Hrs post-study drug administration after 1 month compared to ERPF at 3Hhrs post-study drug administration after 1 dose, sitagliptin vs placebo | 3 Hrs post-administration after 1 month and after 1 dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes, DPP-4 inhibitors, renal sodium excretion