Clinical trial NCT02406443: The INDORSE Study: Inhibition of Dipeptidyl Peptidase IV: Outcomes on Renal Sodium Excretion
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Type 2 Diabetes
Keywords: Type 2 Diabetes, DPP-4 inhibitors, renal sodium excretion
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2015-04-02
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Percent Change in Fractional Excretion of Sodium (FENA)
timeFrame: 3 Hrs post-administration after 1 month and after 1 dose
Secondary outcomes:
measure: Change in Glomerular Filtration Rate (GFR)
timeFrame: 3 Hrs post-administration after 1 month and after 1 dose
measure: Change in Fractional Excretion of Lithium (FELi)
timeFrame: 3 Hrs post-administration after 1 month and after 1 dose
measure: Change From Baseline in SDF-1alpha^1-67 (Intact) Measured by Immunoaffinity and Tandem Mass Spectrometry
timeFrame: 3 Hr vs. baseline after 1 dose
measure: Change From Baseline in SDF-1alpha^3-67 (Truncated) Measured by Tandem Mass Spectrometry With Antibody-based Affinity Enrichment
timeFrame: 3Hrs vs baseline after 1 dose
measure: Change in Systolic Blood Pressure (SBP), Non-invasive Cardiac Output Monitoring
timeFrame: 3 Hrs post-administration after 1 month and after 1 dose
measure: Change in Effective Renal Plasma Flow (ERPF)
timeFrame: 3 Hrs post-administration after 1 month and after 1 dose
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: University Health Network - Division of Nephrology
state: Ontario
Study officials:
affiliation: Lunenfeld Tanenbaum Reserach Institute, Divsion of Endocrinology and Metabolism, University of Toronto
name: Julie Lovshin, MD,PhD
role: STUDY_DIRECTOR
affiliation: Division of Nephrology, University Health Network, University of Toronto
name: David I Cherney, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.