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

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

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Sitaglitpin; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2N2
      • University Health Network - Division of Nephrology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

  1. Type 1 Diabetes,
  2. eGFR <50mL/min/1.73m,
  3. pregnancy or breast feeding,
  4. significant cardiac, pulmonary or liver disease,
  5. prior history of pancreatitis, medullary thyroid cancer, multiple endocrine neoplasia syndromes,
  6. SBP >161 mmHg, 7) DBP >100 mmHg,
  7. alcohol or substance abuse,
  8. states of secondary hypertension.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Health Network, Toronto
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Study Director: Julie Lovshin, MD,PhD, Lunenfeld Tanenbaum Reserach Institute, Divsion of Endocrinology and Metabolism, University of Toronto; Principal Investigator: David I Cherney, MD,PhD, Division of Nephrology, University Health Network, University of Toronto

Publications and helpful links

General Publications

• Lovshin JA, Rajasekeran H, Lytvyn Y, Lovblom LE, Khan S, Alemu R, Locke A, Lai V, He H, Hittle L, Wang W, Drucker DJ, Cherney DZI. Dipeptidyl Peptidase 4 Inhibition Stimulates Distal Tubular Natriuresis and Increases in Circulating SDF-1alpha1-67 in Patients With Type 2 Diabetes. Diabetes Care. 2017 Aug;40(8):1073-1081. doi: 10.2337/dc17-0061. Epub 2017 May 26. Erratum In: Diabetes Care. 2017 Aug 25;:

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): January 1, 2017

Study Registration Dates

• First Submitted: March 30, 2015
• First Submitted That Met QC Criteria: April 1, 2015
• First Posted (Estimate): April 2, 2015

Study Record Updates

• Last Update Posted (Actual): April 5, 2018
• Last Update Submitted That Met QC Criteria: January 9, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: Type 2 Diabetes, DPP-4 inhibitors, renal sodium excretion
• 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; Sitagliptin Phosphate
• Other Study ID Numbers: 14-8616